CN1780841A

CN1780841A - 5,7-diaminopyrazolo[4,3-d]pyrimidines useful in the traetment of hypertension

Info

Publication number: CN1780841A
Application number: CNA2004800114670A
Authority: CN
Inventors: A·S·贝尔; D·G·布朗; D·N·A·福克斯; I·R·马什; A·I·莫雷尔; M·J·帕尔默; C·A·温斯洛
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd; Pfizer Ltd; Pfizer Inc
Priority date: 2003-04-29
Filing date: 2004-04-22
Publication date: 2006-05-31
Anticipated expiration: 2024-04-22
Also published as: ZA200506975B; CN100439371C; GT200400083A; TNSN05276A1; UA80871C2

Abstract

This invention relates to compounds of formula (I).

Description

Can be used for treating hypertensive 5, the 7-diamino-pyrazole is [4,3-d] pyrimidine also

The present invention relates to 5 of series of novel, 7-diamino-pyrazole also [4,3-d] pyrimidine, they are cyclic guanylic acid one phosphoric acid (cGMP)-specific phosphodiesterase enzyme 5 type inhibitor (below be referred to as the PDE-5 inhibitor), they can be used for treating hypertension and other obstacles, also relate to they the preparation method, be used for the intermediate of their preparation, and relate to the composition that contains them and the purposes of described compound and composition.

I) hypertension

Blood pressure (BP) depends on the alone or in combination impact of multiple hemodynamic parameter. Systolic pressure (SBP) is the peak angiosthenia that reaches along with heart contraction. Diastolic pressure (DBP) is the minimum angiosthenia that reaches along with diastole. The difference of SBP and DBP is defined as pulse pressure (pulse pressure, PP).

Hypertension or BP raise and are defined as at least 140mmHg and/or DBP 90mmHg at least of SBP. By this definition, the generality of hypertension in developed country is the about 20% of adult population, rises to about 60-70% in 60 years old or older crowd, and not excessive when measuring in non-clinical setting, most of these hyperpietics have normal BP. There are some to have ISH (ISH) in this 60% senile hypertension population, that is to say that they have SBP and the normal DBP of rising. Hypertension increases relevant (Faga rd, RH with the risk of apoplexy, miocardial infarction, atrial fibrillation, heart failure, peripheral artery disease and renal hypofunction; Am.J. Geriatric Cardiology 11 (1), 23-28,2002; Brown, MJ and Haycock, S; Drugs 59 (Suppl 2), 1-12,2000).

Hypertensive Pathological Physiology there is no final conclusion. It is generally acknowledged that hypertension is result unbalance between heart output and the peripheral vascular opposing, most of hyperpietics have unusual heart output and the periphery opposing that increases, but still uncertain which parameter at first changes (Beevers, Get al.; BMJ 322,912-916,2001).

It is available that high amount of drug is arranged in multiple pharmacology classification, comprise diuretics, alpha-adrenergic antagonist, beta-adrenergic antagonist, calcium channel blocker, ACE (ACE) inhibitor and angiotensin receptor antagonist, but the hypertensive demand of effective treatment not yet is met.

Ii) PDE-5 inhibitor

Vascular endothelial cell secretion nitric oxide (NO). Its vasoactive smooth muscle cell causes the activation of guanylate cyclase and accumulating of cyclic guanosine monophosphate (cGMP). Accumulating of cGMP causes of flaccid muscles and blood vessel dilatation. This expansion has reduced the blood vessel opposing, therefore causes Blood pressure drop.

CGMP is hydrolyzed to guanosine 5 '-one phosphoric acid (GMP) and inactivation by the cGMP-specific phosphodiesterase enzyme. Differentiated a kind of important phosphodiesterase, i.e. PDE5 type (PDE-5). The inhibitor of PDE-5 can reduce the speed of cGMP hydrolysis, therefore strengthens nitric oxide production effect.

Reported the PDE-5 inhibitor of some chemical species, comprise: pyrazolo [4,3-d] pyrimidine-7-ketone (International Patent Application WO 93/06104 of for example having announced, WO 98/49166, WO 99/54333, WO 00/24745, WO 01/27112 and WO 01/27113), pyrazolo [3,4-d] pyrimidine-4-ketone (International Patent Application WO 93/07149 of for example having announced), pyrazolo [4,3-d] pyrimidine (International Patent Application WO 01/18004 of for example having announced), quinazoline-4-ketone (International Patent Application WO 93/12095 of for example having announced), pyrido [3,2-d] pyrimidine-4-ketone (International Patent Application WO 94/05661 of for example having announced), purine-6-ketone (International Patent Application WO 94/00453 of for example having announced), hexahydropyrazine also [2 ', 1 ': 6,1] pyrido [3,4-b] indoles-1,4-diketone (International Patent Application WO 95/19978 of for example having announced) and imidazo [5,1-f] [1,2,4] triazinone (International Patent Application WO 99/24433 of for example having announced).

They have been prompted the medicine as the treatment associated conditions, angina pectoris for example, but the PDE-5 inhibitor not yet is used as treating hypertensive medicine. Known PDE-5 inhibitor can be used for treating male erectile dysfunction, for example silaenafil, Tadalafei and Vardenafil. Still need new PDE-5 inhibitor, particularly improved PDE and the inhibitor of pharmacokinetics and pharmacodynamic properties.

WO 02/00660 and WO 01/18004 disclose has the inhibiting pyrazolo of PDE-5 [4,3-d] pyrimidine, and they can be used for the treatment of the cardiovascular system obstacle.

According to first aspect, the invention provides formula (I) compound

Wherein

R ¹To be selected from R^A、R ^B、R ^CAnd R^DCyclic group, they are separately alternatively by one or more R⁷Group replaces;

R ²Hydrogen or C₁-C ₂Alkyl;

R ³And R⁴C independently of one another₁-C ₈Alkyl, C₂-C ₈Thiazolinyl, C₂-C ₈Alkynyl or C₃-C ₁₀Cycloalkyl, they are separately alternatively by one or more R⁸Group replaces, perhaps R^E, it is alternatively by one or more R⁹Group replaces, perhaps hydrogen;

Perhaps-NR³R ⁴Consist of R^F, it is alternatively by one or more R¹⁰Group replaces;

R ⁵C₁-C ₆Alkyl, C₁-C ₆Haloalkyl, C₂-C ₆Thiazolinyl, C₂-C ₆Alkynyl or C₃-C ₇Cycloalkyl, they are separately alternatively by one or more hydroxyl, C of being selected from₁-C ₆Alkoxyl, C₁-C ₆Halogenated alkoxy, C₃-C ₇Cycloalkyl and C₃-C ₇The group of cycloalkyloxy replaces, perhaps hydrogen;

R ⁶Can be connected to N¹Or N²The place, it is R^6AOr hydrogen;

R ^6AC₁-C ₆Alkyl, C₁-C ₆Haloalkyl, C₂-C ₆Thiazolinyl or C₂-C ₆Alkynyl, they are separately alternatively by C₁-C ₆Alkoxyl, (C₃-C ₆Cycloalkyl) C₁-C ₆Alkoxyl, C₁-C ₆Halogenated alkoxy or or be selected from R^J、R ^K、R ^LAnd R^MCyclic group replace perhaps R^6AR^N、C ₃-C ₇Cycloalkyl or C₃-C ₇Halogenated cycloalkyl, they are separately alternatively by C₁-C ₆Alkoxyl or C₁-C ₆Halogenated alkoxy replaces;

R ⁷Halogeno-group, C₁-C ₆Alkyl, C₁-C ₆Haloalkyl, C₂-C ₆Thiazolinyl, C₂-C ₆Alkynyl, C₃-C ₁₀Cycloalkyl, C₃-C ₁₀Halogenated cycloalkyl, oxo base, phenyl, OR¹²、OC(O)R ¹²、NO ₂、NR ¹²R ¹³、 NR ¹²C(O)R ¹³、NR ¹²CO ₂R ¹⁴、C(O)R ¹²、CO ₂R ¹²、CONR ¹²R ¹³Or CN; R⁸Halogeno-group, phenyl, C₁-C ₆Alkoxyl phenyl, OR¹²、OC(O)R ¹²、NO ₂、NR ¹²R ¹³、 NR ¹²C(O)R ¹³、NR ¹²CO ₂R ¹⁴、C(O)R ¹²、CO ₂R ¹²、CONR ¹²R ¹³、CN、C ₃-C ₆Cycloalkyl, R^GOr R^H, the latter two are alternatively by one or more R⁹Group replaces;

R ⁹C₁-C ₆Alkyl, C₁-C ₆Haloalkyl or CO₂R ¹²；

R ¹⁰Halogeno-group, C₃-C ₁₀Cycloalkyl, C₃-C ₁₀Halogenated cycloalkyl, phenyl, OR¹²、OC(O)R ¹²、 NO ₂、NR ¹²R ¹³、NR ¹²C(O)R ¹³、NR ¹²CO ₂R ¹⁴、C(O)R ¹²、CO ₂R ¹³、CONR ¹²R ¹³, CN, oxo base, C₁-C ₆Alkyl or C₁-C ₆Haloalkyl, the latter two are alternatively by R¹¹Replace;

R ¹¹OH, phenyl, NR¹²R ¹³Or NR¹²CO ₂R ¹⁴；

R ¹²And R¹³Hydrogen, C independently of one another₁-C ₆Alkyl or C₁-C ₆Haloalkyl;

R ¹⁴C₁-C ₆Alkyl or C₁-C ₆Haloalkyl;

R ^AAnd R^JC independently of one another₃-C ₁₀Cycloalkyl or C₃-C ₁₀Cycloalkenyl group, they can be separately monocycle or be many rings when having the annular atoms of right quantity, and they can condense in

(a) monocyclic aromatic ring, it is selected from phenyl ring and contains at the most three heteroatomic 5-or 6-unit heteroaromatic rings that are selected from nitrogen, oxygen and sulphur, perhaps

(b) contain at the most three heteroatomic 5-, 6-or heterolipid family of 7-unit rings that are selected from nitrogen, oxygen and sulphur;

R ^BAnd R^KPhenyl or naphthyl independently of one another, they can condense separately in

(a)C ₅-C ₇Cycloalkyl or C₅-C ₇The cyclenes basic ring,

(b) contain at the most three heteroatomic 5-, 6-or heterolipid family of 7-unit rings that are selected from nitrogen, oxygen and sulphur, perhaps

(c) contain at the most three heteroatomic 5-or 6-unit heteroaromatic rings that are selected from nitrogen, oxygen and sulphur; R^C、R ^LAnd R^NBe independently of one another monocycle or be many ring fillings or the unsaturated ring system of part when having the annular atoms of right quantity, wherein contain 3 to 10 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur, this ring can condense in C₅-C ₇Cycloalkyl or C₅-C ₇Cycloalkenyl group or monocyclic aromatic ring are selected from phenyl ring and contain at the most three heteroatomic 5-or 6-unit heteroaromatic rings that are selected from nitrogen, oxygen and sulphur;

R ^DAnd R^MTo contain at the most three heteroatomic 5-or 6-unit heteroaromatic rings that independently are selected from nitrogen, oxygen and sulphur independently of one another, this ring can further condense in

(a) second contains at the most three heteroatomic 5-or 6-unit heteroaromatic rings that are selected from nitrogen, oxygen and sulphur,

(b)C ₅-C ₇Cycloalkyl or C₅-C ₇The cyclenes basic ring,

(c) contain at the most three heteroatomic 5-, 6-or heterolipid family of 7-unit rings that are selected from nitrogen, oxygen and sulphur, perhaps

(d) phenyl ring;

R ^E、R ^FAnd R^GBe independently of one another monocycle or be many ring fillings ring system when having the annular atoms of right quantity, wherein contain 3 to 10 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur;

R ^HTo contain at the most three heteroatomic 5-or 6-unit heteroaromatic rings that independently are selected from nitrogen, oxygen and sulphur;

Solvate or the polymorphic of its tautomeride or pharmaceutically acceptable salt, described compound or tautomeride.

Unless opposite indication is arranged, alkyl or alkoxyl can be straight or brancheds, contain 1 to 8 carbon atom, preferred 1 to 6,1 to 4 carbon atom particularly. The example of alkyl comprises methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, amyl group and hexyl. The example of alkoxyl comprises methoxyl group, ethyoxyl, isopropoxy and n-butoxy.

Unless opposite indication is arranged, alkenyl or alkynyl can be straight or branched, contains 2 to 8 carbon atoms, preferred 2 to 6,2 to 4 carbon atoms particularly, and can contain at the most 3 can conjugation two keys or three key. The example of thiazolinyl and alkynyl comprises vinyl, pi-allyl, butadienyl and propargyl.

Unless opposite indication is arranged, cycloalkyl or cycloalkyloxy can contain 3 to 10 annular atomses, can be monocycle or be many rings when having the annular atoms of right quantity. The example of cycloalkyl has cyclopropyl, cyclopenta, cyclohexyl and adamantyl.

Unless opposite indication is arranged, cycloalkenyl group can contain 3 to 10 annular atomses, can be monocycle or be many rings when having the annular atoms of right quantity, and can contain at the most 3 two keys. The example of cycloalkenyl group has cyclopentenyl and cyclohexenyl group.

Aryl comprises phenyl, naphthyl, anthryl and phenanthryl.

Unless opposite indication is arranged, heterolipid family cyclic group contains 3 to 10 annular atomses, wherein at the most 4 can be hetero atom, for example nitrogen, oxygen and sulphur, this cyclic group can be saturated or part is undersaturated. The example of heterolipid family cyclic group has Oxyranyle, azetidinyl, tetrahydrofuran base, tiacyclopentane base (thiolanyl), pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, sulfolane base (sulfolanyl), dioxolane base (dioxolanyl), dihydro pyranyl, THP trtrahydropyranyl, piperidyl, pyrazolinyl, pyrazolidinyl, alkyl dioxin, morpholinyl, dithiane base (dithianyl), thiomorpholine base, piperazinyl, azatropylidene base, oxygen azatropylidene base (oxazepinyl), sulphur azatropylidene base (thiazepinyl), thiazolinyl and Diazesuberane base (diazapanyl).

Unless opposite indication is arranged, heteroaryl contains 3 to 10 annular atomses, wherein at the most 4 can be hetero atom, for example nitrogen, oxygen and sulphur. The example of heteroaryl has furyl, thienyl, pyrrole radicals, oxazolyl, thiazolyl, imidazole radicals, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl group, pyridine radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, tetrazole radical, triazine radical. In addition, the term heteroaryl comprises the heteroaryl that condenses, for example benzimidazolyl, benzoxazolyl, imidazopyridyl, benzoxazinyl, benzothiazine Ji, oxazole and pyridine radicals, benzofuranyl, quinolyl, quinazolyl, quinoxalinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepine base, indyl and isoindolyl.

For avoiding feeling uncertain, the heteroaromatic system of oxo base-replacement also is regarded as heteroaryl, such as pyridine ketone group, pyrans ketone group, imidazoline ketone group etc.

Halogeno-group represents fluorine, chlorine, bromine or iodine.

Haloalkyl comprises single haloalkyl, multi-haloalkyl and whole haloalkyl, 2-bromoethyl, 2,2 for example, 2-trifluoroethyl, chlorodifluoramethyl-and trichloromethyl. Halogenated alkoxy comprises single halogenated alkoxy, many halogenated alkoxies and perhalogeno alkoxyl, 2-bromine ethyoxyl, 2,2 for example, 2-trifluoro ethoxy, chlorine difluoro-methoxy and trichlorine methoxyl group. Halogenated cycloalkyl comprises single halogenated cycloalkyl, many halogenated cycloalkyls and perhalogeno cycloalkyl.

Unless opposite indication is arranged, term replaces expression and is replaced by one or more defined groups. Can be selected from a large amount of confessions at substituting group and select in the situation of group, selected group can be identical or different.

A kind of preferred embodiment in, R¹R^A, it is alternatively by one or more R⁷Group replaces;

R ^AC₃-C ₁₀Cycloalkyl, it can be monocycle or be many rings when having the annular atoms of right quantity, and they can condense in

(a) monocyclic aromatic ring is selected from phenyl ring and contains at the most three heteroatomic 5-or 6-unit heteroaromatic rings that are selected from nitrogen, oxygen and sulphur, perhaps

(b) contain at the most three heteroatomic 5-, 6-or heterolipid family of 7-unit rings that are selected from nitrogen, oxygen and sulphur.

Preferably, R^AMonocycle C₃-C ₈Cycloalkyl.

More preferably, R^AMonocycle C₅-C ₇Cycloalkyl.

Most preferably, R^ACyclopenta or cyclohexyl.

In another preferred embodiment, R¹R^B, it is alternatively by one or more R⁷Group replaces.

Preferably, R^BIt is phenyl.

In another preferred embodiment, R¹R^C, it is alternatively by one or more R⁷Group replaces.

Preferably, R^CBe the saturated or undersaturated ring system of part of monocycle, wherein contain 3 to 8 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur.

More preferably, R^CBe the saturated or undersaturated ring system of part of monocycle, contain 5 to 7 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur.

More preferably, R^CBe the saturated ring system of monocycle, contain 5 to 7 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur.

Most preferably, R^CIt is piperidyl.

In another preferred embodiment, R¹R^D, it is alternatively by one or more R⁷Group replaces.

Preferably, R^DTo contain at the most three heteroatomic 5-or 6-unit heteroaromatic rings that independently are selected from nitrogen, oxygen and sulphur.

More preferably, R^DBe to contain the hetero atom that is selected from nitrogen, oxygen and sulphur and in ring, contain alternatively the at the most 5-unit heteroaromatic rings of two nitrogen-atoms, perhaps comprise the 6-unit heteroaromatic rings of 1,2 or 3 nitrogen-atoms.

More preferably, R^DFuryl, thienyl, pyrrole radicals, pyrazolyl, imidazole radicals, Yi Evil azoles Ji, oxazolyl, isothiazolyl, thiazolyl, oxadiazolyl, pyridine radicals, pyridazinyl, pyrimidine radicals or pyrazinyl.

Most preferably, R^DPyrazolyl, imidazole radicals, isoxazolyl, oxazolyl, oxadiazolyl, pyridine radicals, pyridazinyl, pyrimidine radicals or pyrazinyl.

Preferably, R⁷Halogeno-group, C₁-C ₆Alkyl, C₁-C ₆Haloalkyl, oxo base, OR¹²Or CONR¹²R ¹³。

More preferably, R⁷Halogeno-group, C₁-C ₃Alkyl, C₁-C ₃Haloalkyl, oxo base, C₁-C ₃Alkoxyl, hydroxyl or CONH (C₁-C ₃Alkyl).

Most preferably, R⁷Fluoro base, methyl, ethyl, hydroxyl, methoxyl group, propoxyl group, trifluoromethyl, oxo base or CONHMe.

Preferably, R²Hydrogen or methyl.

More preferably, R²Hydrogen.

Preferably, R³Hydrogen, C₁-C ₆Alkyl, it is alternatively by one or more R⁸Group replaces, perhaps R^E, it is alternatively by one or more R⁹Group replaces; R wherein^EBe monocycle or be many rings, saturated ring system when having the annular atoms of right quantity, contain 3 to 7 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur.

More preferably, R³Hydrogen, C₁-C ₄Alkyl, it is alternatively by one or more R⁸Group replaces, perhaps R^E, it is alternatively by one or more R⁹Group replaces; R wherein^EBe the saturated ring system of monocycle, contain 3 to 7 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur.

A kind of preferred embodiment in, R³R^E, it is alternatively by one or more R⁹Group replaces; R wherein^EBe the saturated ring system of monocycle, contain 3 to 7 annular atomses, wherein contain a nitrogen-atoms.

More preferably, R^EAzetidinyl, pyrrolidinyl or piperidyl.

In another preferred embodiment, R³C₁-C ₄Alkyl, it is alternatively by one or more R⁸Group replaces, wherein R⁸Halogeno-group, phenyl, C₁-C ₆Alkoxyl phenyl, OR¹²、 NR ¹²R ¹³、NR ¹²CO ₂R ¹⁴、CO ₂R ¹²、CONR ¹²R ¹³、R ^GOr R^H, the latter two are alternatively by one or more R⁹Group replaces.

More preferably, R⁸Hydroxyl, methoxyl group, methoxyphenyl, NH₂、NHMe、NMe ₂、 NHCO ₂ ^tBu、NMeCO ₂ ^tBu、CO ₂H、CONHMe、R ^GOr R^H, the latter two are alternatively by one or more R⁹Group replaces.

A kind of preferred embodiment in, R⁸R^G, it is alternatively by one or more R⁹Group replaces, wherein R^GBe the saturated ring system of monocycle, contain 3 to 7 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur.

More preferably, R^GBe the saturated ring system of monocycle, contain 3 to 7 annular atomses, wherein contain a nitrogen-atoms and contain alternatively an oxygen atom.

Most preferably, R^GPyrrolidinyl, piperidyl or morpholinyl.

In another preferred embodiment, R⁸R^H, it is alternatively by one or more R⁹Group replaces, wherein R^HTo contain at the most 5-or the 6-unit heteroaromatic rings of two nitrogen-atoms.

More preferably, R^HIt is pyrazolyl.

Preferably, R⁹Methyl or CO₂ ^tBu。

In another preferred embodiment, R³Hydrogen or C₁-C ₄Alkyl, it is alternatively by one or more R⁸Group replaces, perhaps R³Be azetidinyl, pyrrolidinyl or piperidyl, they are separately alternatively by one or more R⁹Group replaces, wherein R⁸Hydroxyl, methoxyl group, methoxyphenyl, NH₂、NHMe、NMe ₂、NHCO ₂ ^tBu、NMeCO ₂ ^tBu、CO ₂H, CONHMe, pyrrolidinyl, piperidyl, morpholinyl or pyrazolyl, rear four alternatively by one or more R⁹Group replaces, wherein R⁹Methyl or CO₂ ^tBu。

A kind of preferred embodiment in, R⁴Hydrogen, C₁-C ₆Alkyl, C₁-C ₆Haloalkyl, C₂-C ₆Thiazolinyl or C₂-C ₆Alkynyl.

More preferably, R⁴Hydrogen, C₁-C ₆Alkyl or C₁-C ₆Haloalkyl.

Most preferably, R⁴Hydrogen, methyl or ethyl.

In another preferred embodiment ,-NR³R ⁴Consist of R^F, it is alternatively by one or more R¹⁰Group replaces, wherein R^FBe monocycle or be many rings, saturated ring system when having the annular atoms of right quantity, contain 3 to 10 annular atomses, wherein contain at least one nitrogen-atoms and contain alternatively other atoms that are selected from oxygen and sulphur.

More preferably, R^FBe monocycle or be many rings, saturated ring system when having the annular atoms of right quantity, contain 3 to 10 annular atomses, wherein contain one or two nitrogen-atoms and contain alternatively other atoms that are selected from oxygen and sulphur.

Most preferably, R^FBe selected from azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, 3-azabicyclic [3.1.0] oneself-3-base, homopiperazine base, 2,5-diazabicylo [2.2.1] heptan-2-base, 2,5-diazabicylo [2.2.2] suffering-2-base, 2,5-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-2-base, 3,8-diazabicylo [3.2.1] oct-3-yl, 3,8-diazabicylo [3.2.1] suffering-8-base, 1,4-diazabicylo [4.3.0] ninth of the ten Heavenly Stems-4-base and Isosorbide-5-Nitrae-diazabicylo [3.2.2] ninth of the ten Heavenly Stems-4-is basic.

Preferably, R¹⁰Halogeno-group, OR¹²、NR ¹²R ¹³、NR ¹²CO ₂R ¹⁴、CO ₂R ¹³, oxo base, C₁-C ₆Alkyl or C₁-C ₆Haloalkyl, the latter two are alternatively by R¹¹Replace.

More preferably, R¹⁰Halogeno-group, methyl, ethyl, isopropyl, hydroxyl, methoxyl group, NH₂、NHMe、NMe ₂、NHCO ₂ ^tBu、CO ₂H、CO ₂ ^tBu, oxo base, benzyl ,-CH₂OH、 -CH ₂NH ₂、-CH ₂NHMe、-CH ₂NMe ₂Or-CH₂NMeCO ₂ ^tBu。

In particularly preferred embodiments ,-NR³R ⁴Consist of the piperazine ring, it is alternatively by one or two methyl substituted, and/or quilt-CH₂-or-CH₂CH ₂The bridging of-group. The bridged piperazine that is fit to comprises 2,5-diazabicylo [2.2.1] heptan-2-base, 2,5-diazabicylo [2.2.2] suffering-2-base, 3,8-diazabicylo [3.2.1] oct-3-yl and 3,8-diazabicylo [3.2.1] suffering-8-basic ring system.

In another preferred embodiment, R³C₁-C ₆Alkyl, it is by a R⁸Group replaces, perhaps R^E, it is by a R⁹Group replaces; Perhaps-NR³R ⁴Consist of cyclic group R^F, it is by a R¹⁰Group replaces, R⁸、R ⁹And R¹⁰All be CO₂H。

Preferably, R⁵C₁-C ₄Alkyl or C₁-C ₄Haloalkyl, they are separately alternatively by hydroxyl, C₁-C ₄Alkoxyl or C₁-C ₄Halogenated alkoxy replaces.

In a kind of preferred embodiment, R⁵C₁-C ₄Alkyl, methylol or C₁-C ₄Alkoxy methyl.

In the preferred embodiment of another kind, R⁵Be methyl, ethyl or propyl group, they are replaced by hydroxyl, methoxy or ethoxy separately alternatively.

Most preferably, R⁵Methyl, ethyl, n-pro-pyl, isopropyl, methylol, methoxy or ethoxyl methyl.

Preferably, R⁶R^6A。

Work as R⁶When being hydrogen, R wherein⁶Be connected to N¹And N²Formula (I) compound at place is tautomeride. These tautomerides will be tending towards all coexistences under solid and solution state, can be not easy to separate. The content of every kind of tautomeride in any equilibrium mixture will depend on the relatively hot mechanical stability of these two kinds of forms. In most of the cases, will to be tending towards be dominant form to the 1H-tautomeride.

Work as R⁶R^6AThe time, can distinguish two kinds of regional isomers (regioisomer) of formula (I) compound. In a kind of preferred invention embodiment, R^6ABe positioned at N¹On, obtain formula (I^A) compound:

In another embodiment, R^6ABe positioned at N²The place obtains formula (I^B) compound:

Preferably, R^6AC₁-C ₆Alkyl or C₁-C ₆Haloalkyl, they are separately alternatively by C₁-C ₆Alkoxyl, C₁-C ₆Halogenated alkoxy, (C₃-C ₆Cycloalkyl) C₁-C ₆Alkoxyl or be selected from R^J、R ^LAnd R^MCyclic group replace perhaps R^6AR^N；

R ^JC₃-C ₇Monocyclic cycloalkyl;

R ^LAnd R^NBe the unsaturated ring system of saturated or part of monocycle independently of one another, contain 4 to 7 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur;

R ^MTo contain at the most three heteroatomic 5-or 6-unit heteroaromatic rings that independently are selected from nitrogen, oxygen and sulphur.

More preferably, R⁶A is C₁-C ₄Alkyl or C₁-C ₄Haloalkyl, they are separately alternatively by C₁-C ₄Alkoxyl, C₁-C ₄Halogenated alkoxy, (C₃-C ₆Cycloalkyl) C₁-C ₆Alkoxyl or be selected from R^J、R ^LAnd R^MCyclic group replace perhaps R^6AR^N；

R ^JCyclopropyl or cyclobutyl;

R ^LAnd R^NBe the saturated ring system of monocycle independently of one another, contain 5 or 6 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur;

R ^MTo contain heteroatomic 5-or the 6-unit heteroaromatic rings that is selected from nitrogen, oxygen and sulphur.

More preferably, R^6AC₁-C ₄Alkyl or C₁-C ₄Haloalkyl, they are separately alternatively by C₁-C ₄Alkoxyl, C₁-C ₄Halogenated alkoxy, (C₃-C ₆Cycloalkyl) methoxyl group or be selected from R^J、R ^LAnd R^MCyclic group replace perhaps R^6AR^N；

R ^JCyclopropyl or cyclobutyl;

R ^LAnd R^NBe the saturated ring system of monocycle independently of one another, contain 5 or 6 annular atomses, wherein contain a hetero atom that is selected from nitrogen, oxygen and sulphur;

R ^M5-or the 6-unit heteroaromatic rings that contains a nitrogen-atoms.

More preferably, R^6AC₁-C ₄Alkyl or C₁-C ₄Haloalkyl, they are separately alternatively by C₁-C ₄Alkoxyl, C₁-C ₄Halogenated alkoxy, (C₃-C ₆Cycloalkyl) methoxyl group, cyclopropyl, cyclobutyl, tetrahydrofuran base, THP trtrahydropyranyl or pyridine radicals replace, perhaps R^6AIt is THP trtrahydropyranyl.

Most preferably, R^6AMethyl, ethyl, isopropyl, isobutyl group, methoxy ethyl, methoxy-propyl, ethoxyethyl group, ethoxycarbonyl propyl, positive propoxy ethyl, isopropoxy ethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoro ethoxy ethyl, oxolane ylmethyl, oxinane ylmethyl, THP trtrahydropyranyl or pyridine radicals methyl.

Particularly preferred embodiment is such formula (I) compound, wherein R⁶To be connected to N¹The R of position^6A，R ^6AIt is 2-(2,2,2-trifluoro ethoxy) ethyl.

The preferred embodiment of formula (I) compound is to be combined with those of two or more above-mentioned preferred versions.

Particularly preferred embodiment is such formula (I) compound, wherein

R ¹To be selected from R^A、R ^B、R ^CAnd R^DCyclic group, they are separately alternatively by one or more

R ⁷Group replaces;

R ²Hydrogen or C₁-C ₂Alkyl;

R ³Hydrogen, C₁-C ₄Alkyl, it is alternatively by one or more R⁸Group replaces, perhaps R^E, it is alternatively by one or more R⁹Group replaces;

R ⁴Hydrogen, C₁-C ₆Alkyl or C₁-C ₆Haloalkyl;

R ⁶R^6AOr hydrogen;

R ^6AC₁-C ₄Alkyl or C₁-C ₄Haloalkyl, they are separately alternatively by C₁-C ₄Alkoxyl, C₁-C ₄Halogenated alkoxy or be selected from R^J、R ^LAnd R^MCyclic group replace perhaps R⁶A is R^N； R ⁷Halogeno-group, C₁-C ₆Alkyl, C₁-C ₆Haloalkyl, C₂-C ₆Thiazolinyl, C₂-C ₆Alkynyl, C₃-C ₁₀Cycloalkyl, C₃-C ₁₀Halogenated cycloalkyl, phenyl, oxo base, OR¹²、OC(O)R ¹²、NO ₂、NR ¹²R ¹³、 NR ¹²C(O)R ¹³、NR ¹²CO ₂R ¹⁴、C(O)R ¹²、CO ₂R ¹²、CONR ¹²R ¹³Or CN;

R ⁸Halogeno-group, phenyl, C₁-C ₆Alkoxyl phenyl, OR¹²、OC(O)R ¹²、NO ₂、NR ¹²R ¹³、 NR ¹²C(O)R ¹³、NR ¹²CO ₂R ¹⁴、C(O)R ¹²、CO ₂R ¹²、CONR ¹²R ¹³、CN、R ^GOr R^H, the latter two are alternatively by one or more R⁹Group replaces;

R ⁹C₁-C ₆Alkyl, C₁-C ₆Haloalkyl or CO₂R ¹²；

R ¹¹OH, phenyl, NR¹²R ¹³Or NR¹²CO ₂R ¹⁴；

R ¹⁴C₁-C ₆Alkyl or C₁-C ₆Haloalkyl;

R ^AMonocycle C₃-C ₈Cycloalkyl;

R ^BIt is phenyl;

R ^CBe the unsaturated ring system of saturated or part of monocycle, contain 3 to 8 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur;

R ^DTo contain at the most three heteroatomic 5-or 6-unit heteroaromatic rings that independently are selected from nitrogen, oxygen and sulphur;

R ^EBe the saturated ring system of monocycle, contain 3 to 7 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur;

R ^FAnd R^GBe independently of one another monocycle or be many rings, saturated ring system when having the annular atoms of right quantity, contain 3 to 10 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur;

R ^JCyclopropyl or cyclobutyl;

More preferably,

R ⁷Group replaces;

R ²Hydrogen or C₁-C ₂Alkyl;

R ⁴Hydrogen, C₁-C ₆Alkyl or C₁-C ₆Haloalkyl;

Perhaps-NR³R ⁴Consist of R^F, it is alternatively by one or more R¹⁰Group replaces; R⁵C₁-C ₄Alkyl or C₁-C ₄Haloalkyl, they are separately alternatively by hydroxyl, C₁-C ₄Alkoxyl or C₁-C ₄Halogenated alkoxy replaces;

R ⁶R^6AOr hydrogen;

R ^6AC₁-C ₄Alkyl or C₁-C ₄Haloalkyl, they are separately alternatively by C₁-C ₄Alkoxyl, C₁-C ₄Halogenated alkoxy or be selected from R^J、R ^LAnd R^MCyclic group replace perhaps R^6AR^N；

R ⁷Halogeno-group, C₁-C ₆Alkyl, C₁-C ₆Haloalkyl, oxo base, OR¹²Or CONR¹²R ¹³；

R ⁸Halogeno-group, phenyl, C₁-C ₆Alkoxyl phenyl, OR¹²、NR ¹²R ¹³、NR ¹²CO ₂R ¹⁴、CO ₂R ¹²、 CONR ¹²R ¹³、R ^GOr R^H, the latter two are alternatively by one or more R⁹Group replaces;

R ⁹C₁-C ₆Alkyl, C₁-C ₆Haloalkyl or CO₂R ¹²；

R ¹¹OH, phenyl, NR¹²R ¹³Or NR¹²CO ₂R ¹⁴；

R ¹⁴C₁-C ₆Alkyl or C₁-C ₆Haloalkyl;

R ^AMonocycle C₅-C ₇Cycloalkyl;

R ^BIt is phenyl;

R ^CBe the saturated ring system of monocycle, contain 5 to 7 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur;

R ^DBe to contain the hetero atom that is selected from nitrogen, oxygen and sulphur and in ring, contain alternatively the at the most 5-unit heteroaromatic rings of two other nitrogen-atoms, perhaps comprise the 6-unit heteroaromatic rings of 1,2 or 3 nitrogen-atoms;

R ^EBe the saturated ring system of monocycle, contain 3 to 7 annular atomses, wherein contain a nitrogen-atoms;

R ^FBe monocycle or be many rings, saturated ring system when having the annular atoms of right quantity, contain 3 to 10 annular atomses, wherein contain at least one nitrogen-atoms and optional other atoms that are selected from oxygen and sulphur;

R ^GBe the saturated ring system of monocycle, contain 3 to 7 annular atomses, wherein at least one is the hetero atom that is selected from nitrogen, oxygen and sulphur;

R ^HTo contain at the most 5-or the 6-unit heteroaromatic rings of two nitrogen-atoms;

Most preferred compound is:

1-(2-ethoxyethyl group)-3-methyl-5-[(3R)-the 3-methylpiperazine-1-yl]-N-pyrimidine-4-base-1H-pyrazolo [4,3-d] pyrimidine-7-amine,

1-(2-ethoxyethyl group)-3-ethyl-5-[(3R)-the 3-methylpiperazine-1-yl]-N-pyrimidine-4-base-1H-pyrazolo [4,3-d] pyrimidine-7-amine,

1-(2-ethoxyethyl group)-3-ethyl-N⁵-methyl-N⁵- (1 - methyl-piperidin-4 - yl)-N⁷- Pyrimidine -4 - Yl-1H-pyrazolo [4,3-d] pyrimidine-5, 7 - diamine,

3 - methyl -5 - [(3R) -3 - methyl-piperazin-1 - yl] -1 - (2 - n-propoxy-ethyl)-N-pyrimidin- -4 - Yl-1H-pyrazolo [4,3-d] pyrimidin-7 - amine,

5 - [(2R, 5S) -2,5 - dimethyl-piperazin-1 - yl] -1 - (2 - ethoxy-ethyl) -3 - methyl-N- Pyrimidin-4 - yl-1H-pyrazolo [4,3-d] pyrimidin-7 - amine,

5 - [(2R, 5S) -2,5 - dimethyl-piperazin-1 - yl] -1 - (2 - ethoxy-ethyl) -3 - ethyl-N- Pyrimidin-4 - yl-1H-pyrazolo [4,3-d] pyrimidin-7 - amine,

1 - (2 - ethoxyethyl)-N⁵3 - dimethyl-N⁷- (4 - methyl-2 - yl)-N⁵- [(3S) -1 - Methyl-pyrrolidin-3 - yl]-1H-pyrazolo [4,3-d] pyrimidine-5, 7 - diamine,

1 - (2 - ethoxy-ethyl) -3 - ethyl-N⁵- Methyl-N⁷- (4 - methyl-2 - Yl)-N⁵- [(3S) -1 - methyl-pyrrolidin-3 - yl]-1H-pyrazolo [4,3-d] pyrimidine -5,7 - two Amines,

1 - (2 - ethoxy-ethyl) -3 - (methoxymethyl) -5 - [(3R) -3 - methyl-piperazin-1 - Yl]-N-(4 - methyl-2 - yl)-1H-pyrazolo [4,3-d] pyrimidin-7 - amine,

1 - (2 - ethoxy-ethyl) -3 - (methoxymethyl)-N⁵，N ⁵- Dimethyl-N⁷- (4 - methyl-pyridine -2 - Yl)-1H-pyrazolo [4,3-d] pyrimidine-5, 7 - diamine,

{1 - (2 - ethoxyethyl) -5 - [N-ethyl-N-methyl-amino] -7 - [(4 - methyl-2 - yl) Amino]-1H-pyrazolo [4,3-d] pyrimidin-3 - yl} methanol,

1 - (2 - isopropoxy-ethyl) -3 - methyl -5 - [(3R) -3 - methyl-piperazin-1 - yl]-N-pyrimidin- -4 - Yl-1H-pyrazolo [4,3-d] pyrimidin-7 - amine,

1 - (2 - ethoxyethyl)-N⁵3 - dimethyl-N⁵- [(3S) -1 - methyl-pyrrolidin-3 - yl]-N⁷- Pyrimidin-4 - yl-1H-pyrazolo [4,3-d] pyrimidine-5, 7 - diamine,

1 - (2 - ethoxy-ethyl) -3 - ethyl-N⁵- Methyl-N⁷- (5 - methyl-2 - Yl)-N⁵- [(3S) -1 - methyl-pyrrolidin-3 - yl]-1H-pyrazolo [4,3-d] pyrimidine -5,7 - two Amines,

1 - methyl -5 - [(3R) -3 - methyl-piperazin-1 - yl] -3 - propyl-N-pyrimidin-4 - yl-1H-pyrazole And [4,3-d] pyrimidin-7 - amine,

N-[5 - ((1R, 4R) -2,5 - diazabicyclo [2.2.1] hept-2 - yl) -1 - (2 - ethoxy-ethyl Yl) -3 - ethyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-pyridin-2 - amine, N-[5 - ((1S, 4S) -2,5 - diazabicyclo [2.2.1] hept-2 - yl) -1 - (2 - ethoxy-ethyl Yl) -3 - ethyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-pyridin-2 - amine, N-{1 - (2 - ethoxy-ethyl) -3 - methoxy-methyl -5 - [(3R) -3 - methyl-piperazin-1 - Yl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -6 - methyl-pyridin-2 - amine, N-{3 - methyl -5 - [(3R) -3 - methyl-piperazin-1 - yl] -1 - [2 - (2,2,2 - trifluoroethoxy) Ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} pyrimidin-4 - yl amine,

N-{5 - (3,8 - diazabicyclo [3.2.1] oct-3 - yl) -3 - methyl-1 - [2 - (2,2,2 - trifluoro- Ethoxy) ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -6 - methyl-pyridin-2 - amine,

N-{3 - ethyl -5 - [(3R) -3 - methyl-piperazin-1 - yl] -1 - [2 - (2,2,2 - trifluoroethoxy) Ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} pyrimidin-4 - yl amine,

N-{3 - methyl-5 - (piperazin-1 - yl) -1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazol Triazolo [4,3-d] pyrimidin-7 - yl} -6 - methyl-pyridin-2 - amine,

1 - {3 - methyl-7 - (6 - methyl-4 - ylamino) -1 - [2 - (2,2,2 - trifluoro-ethoxy) ethyl Yl]-1H-pyrazolo [4,3-d] pyrimidin-5 - yl} piperidin-4 - carboxylic acid,

N-{3 - ethyl -5 - [(3R) -3 - methyl-piperazin-1 - yl] -1 - [2 - (2,2,2 - trifluoroethoxy) Ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} pyridazin-4 - yl amine,

N-{3 - ethyl -5 - [(3R) -3 - methyl-piperazin-1 - yl] -1 - [2 - (2,2,2 - trifluoroethoxy) Ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -2 - methyl-pyrimidin-4 - yl amine,

3 - ethyl-N⁵- Methyl-N⁵- (1 - methyl-piperidin-4 - yl)-N⁷- (6 - methyl-4 - Yl) -1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidine -5,7 - Diamine,

N-{3 - methoxy-methyl -5 - [(3R) -3 - methyl-piperazin-1 - yl] -1 - [2 - (2,2,2 - trifluoroethyl Oxy) ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -6 - methyl-pyridin-2 - amine,

N-{3 - ethoxy-methyl -5 - [(3R) -3 - methyl-piperazin-1 - yl] -1 - [2 - (2,2,2 - trifluoroethyl Oxy) - ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -6 - methyl-pyridin-2 - amine,

N-{3 - methoxy-methyl -5 - [(3R) -3 - methyl-piperazin-1 - yl] -1 - [2 - (2,2,2 - trifluoroethyl Oxy) ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -4 - methyl-pyridin-2 - amine,

1 - {3 - methyl-7 - (4 - methyl-pyridin-2 - yl-amino) -1 - [2 - (2,2,2 - trifluoro-ethoxy) ethyl Yl]-1H-pyrazolo [4,3-d] pyrimidin-5 - yl} piperidin-4 - carboxylic acid,

N-{3 - ethoxy-methyl -5 - [(3R) -3 - methyl-piperazin-1 - yl] - [2 - (2,2,2 - trifluoroethoxy Yl) ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -4 - methyl-pyridin-2 - amine,

1 - {3 - ethyl-7 - (6 - methyl-4 - ylamino) -1 - [2 - (2,2,2 - trifluoro-ethoxy) ethyl Yl]-1H-pyrazolo [4,3-d] pyrimidin-5 - yl} piperidin-4 - carboxylic acid, and

3，N ⁵- Dimethyl-N⁵- (1 - methyl-piperidin-4 - yl)-N⁷- (6 - methyl-4 - Yl) -1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidine -5,7 - Diamine,

Their tautomers and pharmaceutically acceptable salts thereof, said compound or tautomers and solvates Polymorphs.

Formula (I) compounds of the pharmaceutically acceptable salts include the acid addition salts and base salts (including two Salt).

Suitable acid addition salts are generated from the non-toxic salts of the acid generated. Examples include acetic acid Salt, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate, Camphor sulfonate, citrate, oxalate salt (edisylate), ethanesulfonate, fumaric Salts, gluceptate, gluconate, glucuronate, hydroxyl benzophenone acid (hibenzate), Hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, hydrogen phosphate, hydroxyl Ethyl sulfonate, D-and L-lactate, malate, maleate, malonate, methanesulfonamide Formate, methyl sulfate 2 - naphthalenesulfonate, nicotinate, nitrate, orotate, acid flutter , Phosphate, sugar acid, stearate, succinate, sulfate, D-and L-tartaric acid And toluenesulfonate. ...

Overview of suitable salts on, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Wiley-VCH, Weinheim, Germany (2002).

Formula (I) compound a pharmaceutically acceptable salt thereof can be prepared easily, the formula (I) Appropriate solution of the compound with the desired acid or base solutions were mixed together. Salt from the solution Precipitated was collected by filtration, or may be recovered by means of the solvent was evaporated.

According to the present invention, pharmaceutically acceptable solvates include hydrates and wherein the crystalline melting Agent may be isotopomers of solvates, for example, D₂O, acetone-d₆、DMSO-d ₆。

Within the scope of the present invention, there is inclusion (clathrate), ie, drug - hosting embedded with Thereof, and the solvates which the contrary, the content of the drug and host nonstoichiometric The. On such complexes, see J Pharm Sci, 64 (8) ,1269-1288by Haleblian (August 1975).

Hereinafter the formula (I) compounds of the entire title includes its salts and of formula (I) compound, and Its salts solvates and inclusion of the title.

The present invention includes as defined above formula (I) compounds polymorph.

Within the scope of the present invention, there is a so-called formula (I) compounds "prodrugs." Thus, Formula (I) compound itself has some of its derivatives have little or no pharmacological activity, when administered After being metabolized to generate a desired activity of the formula (I) compound. Such derivatives are referred to as "front Pro-drugs. "

According to the present invention, prodrugs can be generated for example, present in the formula (I) compound Functionality of the appropriate techniques known in the art, some of the "front portion" instead of, for example, Such as "Design of Prodrugs", H Bundgaard (Elsevier, 1985) described below.

Finally, some of the formula (I) compound itself may act as the other formula (I) compounds prodrug Thereof.

Contain one or more asymmetric carbon atoms of the formula (I) can exist in two or more compounds Kinds of optical isomers. If the formula (I) compound contains alkenyl or alkenylene group, geometric cis there may / Trans (or Z / E) isomers of compounds containing, for example if the keto group or oxime group, there may be mutual Tautomeric phenomena (tautomerism). Thus, the performance of a single compound may be in On the type of isomerism.

Within the scope of the present invention include formula (I) compound to all optical isomers, geometrical isomers Body and the tautomeric forms, including the performance of more than one type of isomerism of compounds, and a Mixtures of two or more of them.

Cis / trans isomers may be by means well known to the skilled person to be separated by conventional techniques, For example, fractional crystallization and chromatography.

For the preparation / isolation of individual stereoisomers by conventional techniques include those suitable optically pure front A transformant, the racemate (or a salt or derivative thereof racemate) split, for example Li Chiral HPLC, or the diastereomeric salts by fractional crystallization, the salt is a racemate and Suitable optically active acid or base (e.g. tartaric acid) generated by the reaction.

The invention also includes formula (I) compounds, all pharmaceutically acceptable isotopic variations. With Isotopic variant is defined as a, in which at least one atom is the same number of atoms, but Unlike common atomic atomic nature of atoms instead.

Suitable for inclusion in the compounds of the invention include isotopes of hydrogen isotopes, for example As²H and³H; carbon isotope, such as¹³C and¹⁴C; nitrogen isotopes, such as¹⁵N; oxygen Isotopes, such as¹⁷O and¹⁸O; phosphorus isotope, such as³²P; sulfur isotopes, such as³⁵S; Isotopes of fluorine, such as¹⁸F; and chlorine isotopes, such as³⁶Cl。

Isotopes of compounds of the invention are, for example, deuterium, i.e.²H can be replaced by a more stable due to metabolic Large and provide certain therapeutic advantages, such as increasing vivo half-life or reduced dosage requirements, Therefore, in some environments, may be preferred.

Formula (I) Certain isotopic variations of the compounds, for example, those incorporating a radioactive isotope Can be used for drug and / or substrate tissue distribution studies. Due to the easy incorporation and detection, radioisotope Isotope tritium (ie³H) and carbon-14 (ie,¹⁴C) are particularly useful for this purpose.

Formula (I) compounds of the general isotopic variants can be prepared, using appropriate reagents Appropriate isotopic variants techniques known in the art for a conventional technology, or the implementation of class Similar to the embodiment described in Preparation Examples and processes.

Formula (I) compounds can be freeze-dried, spray dried or evaporated to dryness to give crystals Amorphous product or solid material, powder or film. Microwave or radio frequency drying may For this purpose.

Formula (I) compounds are inhibitors of PDE-5. Thus, in another aspect, the invention provides a Formula (I) compound or its tautomers, salts or solvates thereof as a medicament, particularly for the For the treatment of PDE-5 inhibition which are known or can be shown to produce a beneficial effect disease or Disease drugs.

The term "treatment" includes palliative, curative and preventive disposal.

Compounds of the present invention is suitable for the treatment of diseases and conditions including hypertension (including primary Hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, with sugar Diabetes-related hypertension, atherosclerosis and related renal vascular hypertension and high blood Pressure), congestive heart failure, angina (including stable, unstable and variant (Prinzmetal) angina), stroke, coronary artery disease, congestive heart failure, blood Reduced tube open illnesses (such as percutaneous transluminal coronary angioplasty), peripheral vascular Disease, atherosclerosis, nitrate (salt)-induced tolerance, nitrate (salt) Resistance By sex, diabetes, impaired glucose tolerance, metabolic syndrome, obesity, sexual dysfunction (Pack Including male erectile dysfunction, impotence, female sexual arousal disorder, clitoral dysfunction, female sexuality Too few patients, female sexual pain, female orgasm dysfunction and spinal cord injury caused by the sexual Dysfunction), premature birth, preeclampsia, dysmenorrhea, polycystic ovary syndrome, benign forefront Gland hyperplasia, bladder outlet obstruction, incontinence, chronic obstructive pulmonary disease, acute respiratory failure, Bronchitis, chronic asthma, allergic asthma, allergic rhinitis, bowel movement disorders (including Irritable Bowel Syndrome), Kawasaki's syndrome, multiple sclerosis, Alzheimer's disease, bovine Psoriasis, skin necrosis, scarring, fibrosis, pain (especially neuropathic pain), Cancer, metastasis, baldness, fruit clamp esophagus (nutcraker oesophagus), anal fissure And hemorrhoids. ...

In a preferred embodiment, the disease or condition is hypertension. More preferably, it is Hypertension, pulmonary hypertension, secondary hypertension, isolated systolic hypertension, Diabetes-related hypertension, and atherosclerosis-related renal vascular hypertension or high Blood pressure.

In another preferred embodiment, the disease or condition is diabetes.

On the other hand, the present invention provides a treatment of a mammal in the inhibition of PDE-5 is known or can Enough shown to produce a beneficial effect of disorder or condition, the method comprising administering to said mammal Was given a therapeutically effective amount of a compound (I) or a pharmaceutically acceptable salt, solvate Or polymorph thereof.

In another preferred embodiment, the disease or condition is diabetes.

The present compounds can be used alone or in combination with other therapeutic agents. When used with the other Therapeutic agents used in combination, the two drugs may be administered simultaneously or successively a. While giving Drugs include a single dosage form containing both drugs administered in separate dosage forms and the two drugs is substantially Administered simultaneously. Has administration includes administration of both drugs in accordance with the different arrangements, as long as the provision of treatment Treatment period, there can be overlap. For the formula (I) compounds of the co-administered drugs, including Aspirin Aspirin, angiotensin II receptor antagonists (such as losartan, candesartan (Candesartan), telmisartan (telmisartan), valsartan, irbesartan (Irbesartan) and eprosartan (eprosartan)), calcium channel blockers (case Such as amlodipine), β-blockers (ie, β-adrenergic receptor antagonists, such as cable Sotalol, propranolol, timolol, atenolol, carvedilol and metoprolol), CI1027, CCR5 receptor antagonists, imidazolines, soluble guanylate cyclase activators, Diuretics (eg hydrochlorothiazide, torasemide, hydrochlorothiazide, chlorthalidone and amiloride), α-adrenergic antagonists (eg doxazosin), ACE (angiotensin converting enzyme) Inhibitors (such as quinapril, enalapril, lisinopril and ramipril), aldosterone Receptor antagonists (such as eplerenone (eplerenone) and spironolactone), neutral endopeptidase Inhibitors, anti-diabetic agents (such as insulin, sulfonylureas (such as glyburide, glibenclamide Pyrazine and glimepiride), glitazones (such as rosiglitazone and pioglitazone) and A blessing Ming), cholesterol lowering agents (such as atorvastatin, pravastatin, lovastatin, simvastatin Statins, fibrates and rosuvastatin) and α-2-δ ligands (such as gabapentin, Pu Jiaba Lin (pregabalin), [(1R, 5R, 6S) -6 - (aminomethyl) bicyclo [3.2.0] hept-6 - yl] Acetic acid, 3 - (1 - (aminomethyl) cyclohexylmethyl)-4H-[1,2,4] oxadiazol-5 - one, C-[1 - (1H-tetrazol-5 - ylmethyl) cycloheptyl] methylamine, (3S, 4S) - (1 - amino-3 ,4 - Dimethyl - cyclopentyl)-acetic acid, (1α, 3α, 5α) - (3 - (aminomethyl) bicyclo [3.2.0] hept-3 - Yl) acetic acid, (3S, 5R) -3 - amino-5 - methyl-octanoic acid, (3S, 5R) -3 - amino-5 - methyl- Heptanoic acid, (3S, 5R) -3 - amino-5 - methyl-nonanoic acid and (3S, 5R) -3 - amino-5 - methyl-octanoic acid). ...

The present compounds can be used alone or co-administered with other drugs, generally with one Or more pharmaceutically acceptable excipients into the formulation. The term "excipient" in this In addition to the text of the present invention is used to describe any ingredient other than the compound. Choice of excipient will be Large extent, depend on the particular mode of administration.

The compounds can be administered orally. Oral administration may involve swallowing, so of Compounds into the gastrointestinal tract, or oral or sublingual administration may be employed, so compounds from the mouth Directly into the bloodstream.

The formulations suitable for oral administration include solid preparations such as tablets, containing granules, liquid Or powder capsules, lozenges (including liquid-filled), chewing agents, many particles and sodium Rice, gel, membrane (including mucous patch), ovate bodies, sprays and liquid Preparation.

Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as Soft or hard capsules fillers, typically comprising a carrier, for example, water, ethanol, propylene glycol, methyl Carboxymethyl cellulose or a suitable oil, and one or more emulsifying agents and / or suspending agents. Liquid formulations may also Can be prepared by means of regeneration of the solid, for example, prepared from the drug bag.

The compounds can also be used in fast-dissolving, fast-disintegrating dosage forms, such as Expert Opinion in Therapeutic Patents, 11 (6) ,981-986 (Liang And Chen, 2001) in those described.

Tablets according to the present invention, a typical composition may contain:

Ingredient	％w/w
Ingredient	％w/w	Formula (I) compound	10.00*
Microcrystalline cellulose	64.12	Formula (I) compound	10.00*
Microcrystalline cellulose	64.12	Lactose	21.38
Cross-linked sodium carboxymethyl cellulose	3.00	Lactose	21.38
Cross-linked sodium carboxymethyl cellulose	3.00	Magnesium stearate	1.50

* According to regulate the amount of drug activity.

A typical tablet formulation chemists can be prepared by known standard processes, for example, Direct compression, granulation (dry, wet or melt), melt congealing, or extrusion. The tablets may Comprising one or more layers and may be coated or not coated.

Excipients suitable for oral administration include carriers, for example, cellulose, calcium carbonate, Dicalcium phosphate, mannitol and sodium citrate; granulation binders such as polyvinylpyrrolidone, Hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and gelatin; disintegrating agents such as starch glycolate And sodium silicate; lubricants such as magnesium stearate, and stearic acid; wetting agents such as sodium lauryl Sulfate; preservative; antioxidant; flavoring agents; and colorants.

For solid preparations for oral administration may be formulated as immediate and / or modified release. Change Sexual release formulations include delayed - continued - pulse - to control dual - targeting - and programmed release Release. Suitable modified release of the technical details, such as high energy dispersions, osmotic and coated particles, See Verma et al, Pharmaceutical Technology On-line, 25 (2), 1-14 (2001). Other modified release formulations are described in U.S. Patent No.6, 106,864 the.

The invention compounds may also be administered directly into the bloodstream, intramuscular or internal organs. Suitable Together in the means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, interior, Urethra, intradural, intracranial, intramuscular and subcutaneous. Suitable means for parenteral administration include Needle (including microneedle) injection syringe without a needle and infusion techniques.

Parenteral preparations are usually aqueous solutions, which may contain excipients such as salts, carbohydrates Compound and buffering agents (preferably to a pH of 3 to 9), but for some applications, they May be more suitable to be formulated as a sterile non-aqueous or dry form, with a suitable carrier in order to Combination, such as sterile, pyrogen-free water.

Skill in the art using standard pharmaceutical techniques well known can be easily achieved parenterally system Agent was prepared under sterile conditions, for example, freeze-dried.

Processing can be increased by means of a suitable parenteral solution used for the preparation of formula (I) compounds Solubility, for example, spray-dried dispersion energy (WO 01/47495) and / or the use of appropriate The preparation techniques, such as using the solubility enhancer.

Formulations for parenteral administration may be formulated as immediate and / or modified release. Modified release formulations Including delays - continued - pulse - to control dual - targeting - and procedures - released.

The compounds can also be administered topically to the skin or mucous membrane, can be used or transdermal skin Way. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams , Ointments, powder spreading, dressing, foam, film, skin patch, paper sachets, vegetable Into agents, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical vectors Include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin and propylene glycol. Can be combined Penetration enhancer used, see, e.g., Finnin and Morgan, J Pharm Sci, 88 (10), 955-958 (October 1999).

Other means of topical administration include using iontophoresis, electroporation, ultrasound penetration (phonophoresis), ultrasound penetration (sonophoresis) and microneedle or needle-free injection plus For delivery.

Formulations for topical administration may be formulated as immediate and / or modified release. Modified release formulations package Including delay - continued - pulse - to control dual - targeting - and procedures - released. Thus, The compounds can be formulated into various solid forms of administration, such as implanted medical supply store, to enhance For long-term release of the active compound.

The compounds can also be administered intranasally or by inhalation, typically in the form of dry powder (single Using, for example, as a dry blend with lactose in the form of a mixture, or mixed components Particles, such as mixed with phospholipids) from a dry powder inhaler administration, or as aerosol spray Agent, from a pressurized container, pump, spray, atomizer (atomizer) (preferably using electronic water Mechanical atomizers produce a fine mist), or nebulizer (nebuliser), with or without a suitable Propellants, such as two chlorofluorinated methane.

Pressurized container, pump, spray, atomizer (atomizer) or a nebulizer (nebuliser) Comprising the active compound solutions or suspensions, which includes, for example ethanol (optionally aqueous acetic Alcohol), or for the active ingredient dispersion, solubilization, or prolonged release reagents for selection, as the solvent Propellant agent, and optionally a surfactant, such as sorbitan trioleate or oligomer Lactic acid.

In the form of a dry powder or suspension formulation before use to micronized pharmaceutical products appropriate to the Inhalation delivery size (typically less than 5 microns). This can be crushed by means of any suitable way Methods, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nano- Tablets, high pressure homogenization, or spray drying slurry.

Suitable for use in the electronic hydraulics generated fine mist atomizer (atomizer) in a solution of Preparations may contain 1μg to 10mg each pushed the compounds of the invention, pushed the volume can be from 1μl to 100μl range. A typical formulation may contain formula (I) compounds, propylene glycol, sterile Water, ethanol and sodium chloride. The solvent can be used instead of propylene glycol include glycerol and polyethylene glycol.

For use in an inhaler or insufflator of the capsule, blister, and the cartridge (for example, gelatin or HPMC Made) may be formulated to contain a compound of the invention, a suitable powder base (e.g. lactose Or starch) and performance-improving agent (e.g., 1 - leucine, mannitol, or magnesium stearate) powder End mixtures.

Dry powder inhalers and aerosols in the case of delivery of dosage units depending on the metering valve Door. Element according to the present invention is usually so arranged, in which the metered dose or "Every press" Containing 1μg to 20mg formula (I) compound. Overall daily dose will usually 1μg to 80mg Range, which can be administered in a single dose or, more usually in the day as the stars Open doses.

Inhalation / intranasal administration may be formulated into preparations immediate and / or modified release. Modified release Formulations include delayed - continued - pulse - to control dual - targeting - and procedures - released.

The compounds can be administered by the rectal or vaginal, such as suppositories, pessaries or irrigation Bowel preparation form. Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate, Products.

Rectal / vaginal administration may be formulated into preparations immediate and / or modified release. Modified release Formulations include delayed - continued - pulse - to control dual - targeting - and procedures - released.

The invention compounds may also be administered directly to the eye or ear, typically in the form of drops, which In isotonic, pH adjusted sterile saline through the micronised suspension or solution. Other appropriate Together in the eye and the ear administration include ointments, biodegradable (e.g. absorbable condensate Rubber sponges, collagen) and non-biodegradable (e.g. silicone) implants, paper sachets, mirror Tablets and granular or cystic system such niosome or liposomes. Polymer (e.g., crosslinked poly Acrylic acid, polyvinyl alcohol, hyaluronic acid), cellulose polymers (such as hydroxypropyl methylcellulose Cellulose, hydroxyethyl cellulose or methyl cellulose) or a heteropolysaccharide polymer (e.g., agarose gel) With preservatives such as benzalkonium chloride used in combination. Such formulations can also use from Son electroosmosis delivery. ...

The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin or with Polyethylene glycol polymers to improve their solubility, dissolution rate, taste masking, Bioavailability and / or stability.

The compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin or with Polyethylene glycol polymers to improve their solubility, dissolution rate, taste masking, Bioavailability and / or stability....

These doses are based on body weight of about 65 to 70kg of normal human subject being treated. Physician Will be able to easily determine the weight outside this range by treatment, such as infants and the elderly fitness Doses used.

The compounds of the invention can follow the preparation of a variety of ways known manner. Reflected in the following Processes and below, unless the contrary, R¹To R⁶Is defined in the first aspect. This These processes constitute the other aspects of the present invention.

1 1 summarizes the process for the synthesis of formula (I) compound synthesis pathway, particularly Where R⁵Is hydrogen or an unsubstituted alkyl or cycloalkyl group of those compounds of formula (I) compound. Raw material Is the formula (II) pyrazole carboxylic acid. Some of formula (II) compound is a product, others are known in the literature The. If they are unknown, it can be available in the art according to one or more of Preparation, for example, as discussed in Section 2 below those.

Process 1

Step (a)

The formula (II) into the corresponding carboxylic acid of formula (III) amide, which can be directly or preferably Via the acid chloride intermediates. Direct conversion can be achieved, i.e. the coupling agent, for example, Carbodiimide (e.g. dicyclohexyl-carbodiimide or 1 - (3 - dimethylaminopropyl) -3 - ethylcarbodiimide Diimine) in the presence of the hydroxyl optionally triazole, such as the presence of HOBT or HOAT, The acid solution was treated with excess ammonia. Suitable solvents include methylene chloride and ethyl acetate. Indirect conversion can be achieved, i.e. in a suitable solvent such as dichloromethane, washed with oxalyl Chloride and N, N-dimethyl formamide, or treatment with thionyl chloride to form chloride. Then The acid chloride in a suitable solvent, such as dichloromethane, tetrahydrofuran or dioxane was treated with Ammonia gas or aqueous ammonia to give the formula (III) amide. ...

Step (b)

When R⁶Is R^6AWhen, in the N-alkylation step is introduced into the group. You can fit Solvent, at between -20 ℃ -100 ℃ temperature, the formula (III) compound with a base (for example, Such as alkali metal carbonates or bicarbonates, such as potassium carbonate or cesium carbonate) or a tertiary amine (e.g. Triethylamine, N-ethyl diisopropylamine or pyridine) and the appropriate chloride (R^5A-Cl), bromide (R^6A-Br), iodide (R^6A-I), mesylate (R^6A-OSO ₂CH ₃) Or tosylate (R^6A-OSO ₂Tol) for processing. Suitable solvents include ethers, such as tetrahydrofuran and dioxane, Lower alcohols such as methanol, ethanol and butanol, ketones such as acetone and 2 - butanone, N-methyl-pyridine Pyrrolidone, N, N-dimethylformamide and acetonitrile.

As an alternative, may be used as the base an alkali metal hydroxide, such as hydroxide, Sodium or potassium hydroxide. Time Suitable solvents include water and water and water - miscible organic solvent, Mixtures.

As an alternative, an alkali metal (C₁-C ₄) Alcoholate as a base, for example, methanol Sodium or potassium t-butoxide as the base. Suitable solvents include time corresponding lower alcohols (also Methanol for sodium methoxide), ethers such as tetrahydrofuran and dioxane, N-methyl pyrrolidone, N, N-dimethylformamide and acetonitrile.

You can also use a stronger base such as sodium hydride and sodium hexamethyldisilazide or potassium nitride (sodium or potassium hexamethyldisilazide). Suitable solvents time Include ethers, such as tetrahydrofuran and dioxane, N-methyl pyrrolidone and N, N-dimethylformamide Amines.

Reaction may also be carried out under phase transfer conditions, using sodium or potassium hydroxide As the alkali aqueous solution, the organic solvent is methylene chloride or chloroform, or a tetraalkyl ammonium chloride Hydroxide as a phase transfer catalyst.

As an alternative, the conversion effects can be achieved using the Mitsunobu reaction (Organic Reactions 1992,42), wherein the formula (III) compound with the appropriate alcohol R^6A-OH, where appropriate Solvent of the solution was treated with triphenylphosphine and a dialkyl azodicarboxylate (e.g. diethyl azodicarboxylate Ethyl or isopropyl azodicarboxylate) processing. Suitable solvents include tetrahydrofuran and dioxane Alkyl. The reaction is preferably at -10 ℃ between the ambient temperature and the temperature.

Preferably, the formula (III) compound with one equivalent of R^6A-Br and 1 equivalent of potassium carbonate in N, N- Dimethyl formamide, at room temperature for 18 hours or with 1.2 equivalents of R^6A-OH, 1.4 Isopropyl azodicarboxylate equivalents and 1.4 equivalents of triphenylphosphine in tetrahydrofuran, in the 0 ℃ -25 ℃ temperature for 2 hours.

Depends on the specific reagents and conditions chosen, the reaction may be N¹- Or N²- Alkylation Product, or a mixture of both. If the resultant mixture, can be isolated using conventional methods Components, such as chromatography or fractional crystallization.

Step (c)

The formula (IV) reducing the nitro group of the compound of formula (V) with an amine transfer reaction can be for example Move or catalytic hydrogenation or dissolving metal reduction is achieved by means of.

The transfer hydrogenation, in the polar solvent (such as tetrahydrofuran, methanol or ethanol), In the transition metal or transition metal salt catalyst, such as palladium hydroxide or palladium (II) in the presence of Optionally at elevated temperature and pressure, the nitro compound with a suitable hydrogen donor such as ammonium formate Or cyclohexenyl response.

The catalytic hydrogenation, in the transition metal or transition metal salt catalyst, such as palladium or Raney In the presence of Raney nickel, optionally under high pressure, the nitro compound in a polar solvent, such as tetrakis Tetrahydrofuran, methanol or ethanol was stirred under a hydrogen atmosphere. Catalyst may be a solution (both A catalyst) or suspension (non-homogeneous catalyst).

For dissolving metal reduction, in the acid, such as acetic acid or hydrochloric acid in the presence of the nitro group Compound in ethanol was treated with a suitable reactive metal, such as zinc or tin treatment. Can also Use other reducing agents such as tin chloride (II).

Preferably, the formula (IV) compound in methanol or ethanol was treated with 10% (by weight) Phi Pd (OH)₂Carbon and 5 equivalents of ammonium treatment, the mixture was heated under reflux for 2 to 18 Small Time.

Step (d)

Optionally, under high pressure, the pyrazole amide (V) with phosgene or its equivalent, such as 1,1 '- Carbonyldiimidazole, trichloromethyl chloroformate or bis (trichloromethyl) carbonate in a suitable solvent Was stirred at ambient temperature and the boiling point of the solvent is stirred at a temperature 2-18 hours, to obtain Corresponding to the formula (VI) pyrazolo pyrimidinedione. Suitable solvents include acetonitrile, dichloromethane, and N, N-dimethylformamide. Preferably, the dione and 1-2 equivalents of acetic carbonyldiimidazole Nitriles, N, N-dimethylformamide or methylene chloride at a temperature of 50 ℃ -80 ℃ heated at 18 Hours.

Step (e)

A tertiary amine such as N-ethyl diisopropylamine, N-methylmorpholine, triethylamine or N, N-dimethyl The presence of aniline at elevated temperature, the formula (VI) with a large excess of the appropriate dione chloride Agent such as phosphorus oxychloride (POCl₃) Or phenyl phosphonic dichloride (PhP (O) Cl₂) Processing 8-48 hours. To obtain the corresponding formula (VII) dichloro-pyrazolo pyrimidine. May optionally be added to N, N-dimethylformamide, Amide as a catalyst. As an alternative, in a suitable solvent, in the four alkyl chloride Ammonium, for example, the presence of tetraethylammonium chloride, at elevated temperatures, the diketone with POCl₃Or PhP (O) Cl₂Treatment. Suitable solvents include acetonitrile and propionitrile.

Preferably, in propionitrile at reflux, the diketone with 10-30 equivalents of POCl₃And 3 -5 Equivalent tetraethylammonium chloride treatment 4-18 hours.

Step (f)

The formula (VII) dichloride, an amine HNR¹R ²With an excess of a tertiary amine such as N-ethyl diisopropylamine, N-methyl morpholine or triethylamine in a suitable solvent at ambient temperature or elevated temperatures was stirred for 1 To 24 hours, to obtain the corresponding formula (VIII) compound. Suitable solvents include methylene chloride, Methyl sulfoxide, N, N-dimethylformamide, tetrahydrofuran and N-methylpyrrolidone.

As an alternative, the amine HNR¹R ²In a suitable solvent is treated with butyllithium or Rokko Sodium bis silicon nitride at a low temperature treatment, the resulting solution was added to the dichloride. Suitable Solvents include tetrahydrofuran, dioxane, and N-methyl pyrrolidone.

Preferably, in dichloromethane, dimethylsulfoxide or dimethylsulfoxide with N-methyl pyrrolidine Ketone mixture, the dichloride with 3-5 equivalents of an amine HNR¹R ²And optionally 3-5 when Amount of N-ethyl diisopropylamine under treatment at 20-90 ℃ 18 hours, or 2-4 equivalents HNR¹R ²In tetrahydrofuran was treated with an equimolar amount of butyllithium or sodium hexamethyldisilazide nitriding treatment, Added 1 equivalent of the dichloride, and the mixture was stirred at 0 ℃ temperature between room temperature and stirred for 2 To 3 hours.

Can figure that, as the R¹Any substituents on functional groups, in particular any primary Or secondary amino groups may need to be protected in order to successfully carry out the reaction. Suitable protection Groups are known in the art, such as those described in "Protective Groups in Organic Synthesis ", Greene, TWand Wutts, PGM, 3rd edition, John Wiley & Sons, Ltd, Chichester, 1999 in the. Primary and secondary amine protecting group of real Examples include t-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBZ or Z) and 9 - fluorenyl-methoxycarbonyl- (Fmoc). Carboxylic acids can be used as their methyl, ethyl, benzyl or t-butyl ester form by Protection. Alcohol may be used as ester or ether derivatives of protected form.

Step (g)

The monochloride (VIII) with an amine HNR³R ⁴The monochloride (VIII) with an amine HNR...³R ⁴The monochloride (VIII) with an amine HNR...

As an alternative, the reaction can be carried out under microwave irradiation.

Preferred conditions are: in dimethyl sulfoxide or N-methyl pyrrolidone, optionally the dense Sealed container, said a chloride with 3-5 equivalents of an amine HNR³R ⁴And optionally a 3 - 5 equivalents of N-ethyl diisopropylamine under treatment at 80-125 ℃ 12-18 hours; or dimethyl Sulfoxide or N-methyl pyrrolidone, optionally in a sealed container, the monochloride With 3-5 equivalents of an amine HNR³R ⁴And 1 equivalent of cesium fluoride at 100-120 ℃ under treatment; or N-methyl pyrrolidone, under microwave irradiation, the one with 3-5 equivalents of an amine HNR chloride³R ⁴And optionally with 3-5 equivalents of N-ethyldiisopropylamine and / or optionally in cesium fluoride or tetraethylammonium Group in the presence of ammonium fluoride for 40 minutes.

Is to be appreciated that, regarding the above step (f),-NR³R ⁴In any functional group, especially Not be any primary or secondary amino groups may need to be protected in order to successfully carry out the reaction.

In some cases, it is possible in accordance with the "one-pot" (one-pot) operation proceeds to step (f) And (g) transformation of the role, that is, without isolation of the formula (VIII) monochloride. The formula (VII) of the Compound with an amine HNR¹R ²Processing, in step (f) above, and to the mixture was added an amine HNR³R ⁴, Reaction as in step (g) for the forward.

When used during the synthesis of one or more protecting group, there will be to protect the final Care programs, to expose the target compounds functional groups. This solution may be a single operation or Who can be divided into several steps. You can also operate with an earlier synthesis combined.

Deprotection are well known in the art, such as "Protective Groups in Organic Synthesis ", Greene, TWand Wutts, PGM, 3rd edition, John Wiley & Sons, Ltd, Chichester, 1999 described above. For example, tert-butoxycarbonyl group - Protected amine and carboxylic acid tert-butyl ester can be deprotected, that is, in a suitable solvent, with Acid such as trifluoroacetic acid or anhydrous hydrogen chloride, benzyloxycarbonyl - protected benzyl amine and carboxylic acid Esters can make use of the catalytic hydrogenolysis to protect, 9 - fluorenyl-methoxycarbonyl - protected amine can borrow Helps to protect piperidine, carboxylic acid methyl and ethyl esters can be by means of an alkali metal hydroxide at Management to protect.

Preferably, the tert-butoxycarbonyl group and t-butyl protecting group is removed such that in methylene Methane at room temperature, treated with trifluoroacetic acid 1-18 hours, or the t-butyloxycarbonyl Protecting group, in the dioxane at room temperature, treated with excess hydrogen chloride for 18 hours. Benzyl protecting group is preferably removed so that the Pd (OH)₂In the presence of ethanol Hydrogen chloride, in the room temperature is hydrogenated at 60psi for 18 hours.

2 Scheme 2 summarizes two methods, the Knorr and the Pechmann synthesis, They can be used for synthesis of formula (II) pyrazole carboxylic acid. You can also use other methods known in the art.

Process 2

Step (h)

As a raw material for synthesis Knorr pyrazole formula (X) 1,3 - dione can cross Claisen Condensation from the corresponding Formula (IX) methyl ketone was prepared. In a suitable solvent in the existence of a suitable base Next, the formula (IX) dimethyl ketone and methyl oxalate reaction. Suitable solvents include ethers, such as Tetrahydrofuran. Suitable bases include sodium hydride, potassium t-butoxide and lithium diisopropylamide. As for Generations of selection, using sodium methoxide as a base and methanol as the solvent.

Step (i)

Can follow the known Knorr pyrazole synthesis method, the formula (X) 1,3 - dione and hydrazine counter , To give the formula (XI) pyrazole.

Is to be appreciated that, a substituted hydrazine R^6ANHNH ₂Can also be used Knorr pyrazole synthesis , And the resulting N-alkylated by the formula (XI) compounds like. Usually generates N¹- And N²- Alkyl Of the mixture of products, can be isolated using conventional components, such as chromatography or fractional Results Crystal.

Below under step (l) and (m) of the method of hydrolysis and nitrification followed according to the above Part 1 of step (a) of the method to generate amides of formula (IV) compound, without first Some of the steps (b) alkylation reaction.

Step (j)

In the Pechmann pyrazole synthesis in this variation, the formula (XII) Diazo Methyl and C, to give formula (XI) pyrazole. Formula (XII) by known diazonium compound Methods, for example by N-arylsulfonyl-N-nitroso derivatives from the corresponding primary amine R⁵CH ₂NH ₂Thereof.

Step (k)

In the Pechmann pyrazole synthesis variant of this alternative, the formula (XIII) with acetylene Diazo acetate, to give formula (XI) pyrazole.

Step (l)

Formula (XI) hydrolysis of the ester compound of formula (XIV) compound. Transformation of the role can Easily done so, that in a suitable solvent at about 10 ℃ temperature between the boiling point of the solvent Degrees, the formula (XI) compound with an alkali metal hydroxide (such as lithium hydroxide, sodium hydroxide Or potassium hydroxide) process. Suitable solvents include water, methanol, ethanol and water and methanol, A mixture of ethanol, tetrahydrofuran and dioxane.

Step (m)

Pyrazole nitrification is well known. The formula (XIV) compound nitrating agent such as nitric acid Or a mixture of nitric acid and sulfuric acid, to give the formula (II) compound.

3 Process 3 provides a synthesis pathway process variations, which can be used to synthesize R⁶Is R^6AThe formula (I) compounds in which the group is introduced in the last step.

Process 3

Step (n)

Some of the steps in accordance with paragraph 1 (b) above method can be of formula (I^C) Compound, also Where R⁶Is hydrogen, the formula (I) compounds are converted to N-alkylation of formula (I^A) And (I^B) Compound. When the reaction of two products (I^A) And (I^B) Of the mixture, it can be isolated using standard techniques We. More reactive alkylating agents tends to promote the use of N²- Substituted formula (I^B) Compound Generation.

4 The method of Schemes 1 and 2 can generally be used for the synthesis in which R⁵Is hydrogen or an unsubstituted Alkyl or cycloalkyl group of the formula (I) compound. It can also be used for synthesis of other Formula (I) compound, Provided that R⁵In any functional group is involved in chemical operations can be compatible. For example, Polyfluoroalkyl and perfluoroalkyl groups are likely to be compatible, as are ether functional groups, if away from the Pyrazolopyrimidine nucleus is even more so. However, in some cases, may be required or necessary Intermediate stage of the synthesis in general, the introduction or modification of R⁵. Process 4-11 below describes the representation Methods. Is to be appreciated that the conversion effect of the many steps in the overall synthesis may not Those exemplified for the point.

4 summarizes the process in which the final step in the introduction of cross-coupling reaction with radicals R⁵The formula (I) synthesis pathway. This method is particularly suitable for R⁵In pyrazolopyrimidine nuclear connection point is Branched or unsaturated situation. According to this method, by first introducing their alkenyl and cycloalkenyl Base analogs, and in the subsequent catalytic hydrogenation step in undesirable reduction of double bonds, can also be To give the saturated alkyl and cycloalkyl.

Process 4

Step (o)

Procedure in accordance with paragraph 1 (a) above method, the commercially available 4 - nitro - (2H) - pyrazole-3 - carboxylic acid to 4 - nitro - (2H) - pyrazole-3 - carboxamide.

Step (p)

Some of the steps in accordance with paragraph 1 (b) the method of formula (IV^A) Compound, also Where R⁵Is hydrogen, the formula (IV) compound.

Step (q)

Some of the steps in accordance with paragraph 1 (c) and (d) the method of formula (VI^A) Compound, That is where R⁵Is hydrogen, the formula (VI) compounds.

Step (r)

Formula (VI^A) Can be prepared by the following method to obtain the corresponding brominated formula (XV) Compound Was: In the N, N-dimethyl formamide, at a high temperature, with N-bromosuccinimide treatment, or Those in acetic acid under reflux with an excess of bromine and treated with sodium acetate. Preferably, the N, N-two Dimethylformamide, at 50 ℃, the formula (VI^A) Compound with N-bromosuccinimide treatment 18 hours.

Step (s)

Some of the steps in accordance with paragraph 1 (e), (f) and (g) the method of formula (XVI) of Thereof.

Step (t)

Can make the formula (XVI) compounds with a suitable reagent R⁵Coupling-M, where M is a metal, Metal derivative or a boron derivative such as: lithium (M = Li); halogenated magnesium, in particular magnesium chloride, Magnesium bromide and magnesium iodide (M = ClMg, BrMg and IMg); halogenated zinc, especially zinc chloride, Zinc bromide and zinc iodide (M = ClZn, BrZn and IZn); trialkyl tin, such as tri-n-butyl Tin (M = n-Bu₃Sn); dialkyl boron, for example, diethyl boron (M = Et₂B); and dialkoxy Boron, such as boron dimethoxyethane (M = (H₃CO) ₂B). Reaction is generally a transition metal catalyst, Such as palladium or nickel or their derivatives in the presence of, and may be additionally required base The use of a base such as potassium carbonate, cesium fluoride or triethylamine. Representative coupling methods include Suzuki and Stille programs, are described in detail in "Metal-Catalysed Cross-Coupling Reactions ", F.Diederich (ed.), Wiley-VCH, 1998 (And references cited therein) in.

5 5 summarizes the process for the preparation of particularly wherein R⁵Is a hydroxymethyl group, an alkoxysilyl Group, a haloalkoxy group or an alkoxymethyl group ring of the formula (I) compound synthesis pathway. In the flow Cheng 5, X represents a leaving group such as chlorine, bromine or iodine atom or an alkyl group, an aryl group or a full Fluoroalkyl sulfonic acid ester group (e.g. mesylate, tosylate or triflate group Group), R^aRepresents an alkyl group, a cycloalkyl group or a haloalkyl group.

Process 5

Step (u)

Step (u)...

Step (v)

In accordance with Part 1 of step (g) method from the formula (XVIII) an alcohol of formula (ID) compounds Material, that is where R⁵Is hydroxymethyl, of formula (I) compound.

Step (w)

Wherein X is Br, formula (XIX) may be prepared by the compound, from the formula (XVIII) alcohol ON Beginning, optionally in the presence of pyridine, in a suitable solvent, such as diethyl ether, dichloromethane Or propionitrile, with hydrogen bromide or triphenylphosphine and bromine, tetrabromomethane or N-bromosuccinimide Mixture processed. Preferably, in dichloromethane, at room temperature, the alcohol with triphenylphosphine And four methyl bromide for 1 hour.

Wherein X is Cl in formula (XIX) may be prepared by the compound, that is, in a suitable solvent, Such as dichloromethane, from the formula (XVIII) starting alcohol with thionyl chloride, phosphorus trichloride or triphenyl Phosphine with N-chlorosuccinimide treated with a mixture. Preferably, in dichloromethane, to the Alcohol treatment with excess thionyl chloride was 2-18 hours.

Wherein X is I, formula (XIX) compounds from the corresponding starting bromide or chloride, By treatment with sodium iodide to prepare.

Wherein X is alkyl sulfonate, aryl sulfonate ester or perfluoroalkyl sulfonate formula (XIX) Compounds can be prepared, i.e. a tertiary amine, such as triethylamine, N-ethyl diisopropylamine or N- Presence methylmorpholine, in a suitable solvent such as dichloromethane, from the formula (XVIII) alcohol ON Beginning with a sulfonyl chloride or an acid anhydride (e.g. methanesulfonyl chloride, tosyl chloride or trifluoromethanesulfonic anhydride) Treatment. As an alternative, pyridine as a solvent, in this case without the With a tertiary amine.

Step (x)

The corresponding formula (XIX) with a compound of sodium or potassium alcoholate NaOR^aOr KOR^aTreatment, In formula (XX) compound. As an alternative, can be formula (XIX) with an excess of an alcohol compound R^aOH and a catalyst such as silver tetrafluoroborate (AgBF₄) Processing. Suitable solvents include acetonitrile, N-methyl-pyrrolidone and N, N-dimethylformamide. As an alternative, you can use alcohol R^aOH as the solvent, as long as it can be easily removed after the reaction (for example by means of evaporation) can.

Preferably, the N, N-dimethylformamide, or R^aOH, in the room temperature, wherein X is Cl or Br of formula (XIX) with an excess of the compound NaOR^a30 minutes to 72 hours.

Step (y)

Formula (XX) compounds from formula (XVIII) starting primary alcohol, similar to the above by using Part (y) the methods discussed with an alkylating agent R^a-X reactions in the system. Thus, of the formula (XVIII) in a suitable alcohol solvent (e.g. N, N-dimethylformamide or acetonitrile) in a solution of With a strong base, such as sodium hydride, an alcohol, sodium and then with an alkylating agent R^a-X treatment.

Will be appreciated that that effect this transformation can be used the formula (I^D) Primary alcohol as a raw material Proceeds, the resulting transformation of the role of formula (I^E) To generate the compound.

Step (z)

Part according to the first step (g) of the method, from the formula (XX) to obtain an alcohol of formula (I^E) Compound, That is where R⁵Is R^aOCH ₂- Of formula (I) compound.

6 of the formula (XVII^A) Acrylate, wherein R is⁶Connected to the N¹- Position of the formula (XVII) Compound Material, and the formula (XVII^B) Acrylate, wherein R is⁶Connected to the N²- Position of the formula (XVII) compounds, Can follow the process 6 summarizes the methods to be prepared.

Process 6

Step (aa)

Some of the steps in accordance with paragraph 1 (b) above method capable of reacting 4 - nitropyrazole -3,5 - two Acid dimethyl ester N-alkylation occurs, the diethyl ester can easily follow the published international Patent Application WO 00/24745 was prepared as described (see page 48 Preparation Example 2). Will be able to To understand that the hydrolysis of ester groups of the transesterification and the sensitivity means that no Can be used alkali metal hydroxides and alcoholates (except methanolate) as a base, and is not Make the water and alcohols (other than methanol) as a solvent or co-solvent.

Because the two nitrogen atoms of pyrazole are equivalent, and therefore obtained a single alkylated product.

Step (bb)

According Chamberset al. (J.Org.Chem.50 ,4736-4738, 1985) of the Method, using one equivalent of an alkali metal hydroxide selective hydrolysis of formula (XXI) diester cleavage with substituted Adjacent nitrogen ester of formula (XXII) monoacid.

Preferably, in methanol, at room temperature, the diester with 1 equivalent of potassium hydroxide 18 hours.

Step (cc)

Part according to the first step (b) to (f) of the method, from the formula (XXII) to obtain the compound Formula (XVII^A) Compounds wherein R is⁶Connected pyrazolopyrimidine N¹- Position of the formula (XVII) Compounds.

-NR ¹R ²Groups introduced preferably through in DMSO, at 30 ℃, the Corresponding dichloride with 3-5 equivalents of HNR¹R ²Achieved for 1 hour.

Step (dd)

Formula (XXIII) can be prepared by the presence of a mineral acid, the formula (XXII) with a monoacid Or methacrylic acid tert-butyl ester prepared by treatment.

Step (ee)

2 in accordance with above step (1) above was hydrolyzed formula (XXIII) methyl compound Ester, according to section 1 above and then steps (a) to (d) obtained as described monoacid modified to give The formula (XXIV) in N²- Pyrazolopyrimidine substituted 5,7 - dione.

Step (ff)

With an acid such as trifluoroacetic acid or hydrogen chloride in a suitable solvent, such as dioxane in Lysis solution treatment to formula (XXIV) the compound tert-butyl ester. Any well known in the art Methods, such as oxalyl chloride or thionyl chloride to generate chloride, followed by treatment with methanol or Methanol and carbodiimide process, and the resulting acid converted to the methyl ester. Then as mentioned in paragraph 1 Some of the steps (e) and (f) the methyl ester of the process of formula (XVII^B) Compound.

7 In the amine HNR¹R ²Only weakly nucleophilic case, for example when R¹Is a pyrimidine or pyridine Piperazine ring, the flow of the synthetic route 6 may lower yield. In these cases, it is necessary to The introduction of the-NR¹R ²Ester group before the group reduction, as described in process 7.

Process 7

Step (gg)

In accordance with Part 1 above step (b) to (e) of the method, from formula (XXII) compound Obtain formula (XXV) compound.

Step (hh)

Some of the steps in accordance with paragraph 5 (v) method from formula (XXV) a compound of formula (XXVI) compound.

Step (ii)

And protecting the primary alcohol of formula (XXVII), wherein PG is an alcohol protecting group. Preferred protecting groups are trialkylsilyl groups, especially t-butyl dimethylsilyl group. Preferably, in dichloromethane, at room temperature, treated with 1.1 equivalents of the t-butyl alcohol, dimethyl Silyl chloride and 1.1 equivalents of imidazole for 18 hours.

Step (jj)

In accordance with Part 1 above step (f) method from formula (XXVII) compounds obtained Formula (XXVIII) compound.

Step (kk)

Using the appropriate conditions for the formula (XXVIII) deprotecting a compound of formula (XVIII) Job Alcohol. When PG is a trialkylsilyl group, it can be by using a fluoride salt (e.g. tetrabutylammonium Ammonium fluoride) treatment, or treatment with a solution of hydrogen chloride in methanol is removed. Preferably, when the PG Is t-butyl dimethylsilyl group, it is in tetrahydrofuran, at room temperature with 2 equivalents of tetrabutylammonium fluoride for 18 hours or in methanol at room temperature, chloride Hydrogen for 18 h and removed.

8 of the formula (XVIII) and (ID) can be oxidized to the corresponding alcohols of formula (XXIX) aldehyde, they In particular of formula (I) compounds used in the preparation of multiple intermediates. Some, such as the role of representative conversion process 8 shows. Unless indicated to the contrary, in the process 8 to 11, Y is C1 or-NR³R ⁴, Can be Preferably Cl.

Process 8

Step (ll)

Formula (XIX) oxidation of alcohol can be achieved, that the use of Cr (VI) reagents, such as chlorine Pyridinium, Swern oxidation of dimethyl sulfoxide solution of the activating reagent, hypervalent iodine reagents, For example, Dess-Martin periodinane, or tetra-n-propyl perruthenate and N-methylmorpholine Morpholine-N-oxide in combination, in a suitable solvent at 0 ℃ temperature between ambient temperature and the Manner. Suitable solvents include methylene chloride.

The preferred reagent is Dess-Martin periodinane.

In principle, the formula (XXIX) can also be at low aldehyde using DIBAL reduction to the corresponding ester Preparation, but in fact it is difficult to restore the function terminates in aldehyde stage, primary alcohols are generally produced mainly Thereof.

Step (mm)

Formula (XXIX) with an aldehyde reagent R Geli Ya^bMgHal wherein R^bIs alkyl or cycloalkyl group, Hal is Cl, Br or I, or with an organolithium reagent R^bLi, to give formula (XXX) a secondary alcohol.

Wherein Y is-NR³R ⁴Of formula (XXX) wherein R is itself a compound⁵Is alkyl substituted by hydroxy Group of the formula (I) compound.

Step (nn)

5 can be displayed in the section on primary alcohol analogs discussed processing formula (XXX) compound. For example, in accordance with Section 5 above step (x) and (y) or fifth part of the steps (z) said square Method are alkylated formula (XXXI) compound.

Another possibility is not illustrated in Scheme 8, it is the use of step (11) in the oxygen Of the secondary alcohol to give ketones, and may be in a similar formula (XXIX) of aldehyde further modified manner.

Step (oo)

Wittig reaction using the method of the formula (XXIX) with a phosphorane aldehyde reagent Ph₃P：C(R ^c)R ^dProcessing, in which R^cAnd R^dIs hydrogen, alkyl or cycloalkyl group of the formula (XXXII) compound Pyrazolo exists with a double bond adjacent pyrimidine nucleus.

When R^aIs CH (R^c)R ^d, They can make use of an acid-catalyzed dehydration from formula (XXX) alcohol or By means of the role of base-catalyzed elimination from the corresponding chloride or mesylate compound prepared in a similar Thereof.

Step (pp)

If it is not required in the final product, then can make use of the catalytic hydrogenation reduction Formula (XXXII) in the compounds of the double bond.

Step (qq)

In step (oo) Wittig reaction with (methoxymethylene) triphenylphosphorane to give To formula (XXXIV) enol ether.

Step (rr)

Formula (XXXIV) allyl ether solution in the acid hydrolysis of formula (XXXV) aldehyde. You can then According to above with respect to formula (XXIX) in the same manner as discussed aldehyde modified them.

9 of the formula (XXIX) can also be an aldehyde homologation to give esters, as described in Scheme 9. However After 5 and 8 according to the above method of modifying a portion of said resulting ester of formula (I) compound.

Process 9

Step (ss)

In tetrahydrofuran, of the formula (XXIX) aldehyde with methyl - (methylthio) methyl sulfoxide (CH₃SCH ₂S(O)CH ₃) And triton B, to give the formula (XXXVI) intermediates.

Step (tt)

The formula (XXXVI) with methanol and acetyl chloride intermediate, to give formula (XXXVII) acrylate.

Step (uu)

Formula (XXIX) can follow the aldehyde Wittig, Horner or Wadsworth-Horner-Emmons reaction of the phosphorus reagent solution, into the formula (XXXVIII) acrylate. The reagent is prepared, that is, in a suitable solvent such as tetrahydro- Furan, the triphenylphosphonium salt Ph₃P ⁺CH ₂CO ₂CH ₃.X ^-(Wittig), phosphine oxides Ph₂P(O)CH ₂CO ₂CH ₃(Horner) or a phosphonate (EtO)₂P(O)CH ₂CO ₂CH ₃(Wadsworth-Horner-Emmons) with a base such as butyl lithium, dialkylamino lithium or an alkali metal Alcoholates processing.

This method is not limited to the α-substituted acrylic acid ester. Use alkyl - substituted phosphorus test Agents such as Ph₃P ⁺CH(R)CO ₂CH ₃.X ^-Or the equivalent phosphine oxide or phosphonate esters (wherein R Is an alkyl group) can be obtained the corresponding α-alkyl acrylate derivative.

Formula (XXIX) aldehyde to the formula (XXXVIII) acrylate conversion can follow Knoevenagel condensation method with malonate derivative achieved.

Step (vv)

Reduction (XXXVIII) carbon - carbon double bond of formula (XXXIX) compound can be done, That the transition metal catalyst such as palladium, platinum or nickel in the presence of molecular hydrogen using catalytic Hydrogenated.

Also of the formula (XXXVIII) with an alkyl acrylate, copper reagent of formula (XXXIX) Compound analogues, and pyrimidine in the pyrazole ring system introduced on adjacent carbon atoms, an alkyl group Substituent, or a sulfonium ylide or carbene equivalent treatment, to give 2 - (pyrazol-pyrimidin-yl) - Cyclopropane-1 - methyl ester derivative.

10 of the formula (XXXVII) homologation of esters can also be prepared using the process described in 10.

Process 10

Step (ww)

Some of the steps in accordance with paragraph 2 (n) method, may be hydrolyzed formula (XVII) and (XXXX) The methyl ester of the formula (XXXXI) acid (according to section 1 above step (g) of the method, From the formula (XVII) ester of formula (XXXX) ester).

Step (xx)

In accordance with the Arndt-Eistert reaction method, you can make the formula (XXXXI) acid homologation. Will be the Said carboxylic acid to a reactive intermediate, such as acid chloride (by reaction with oxalyl chloride) or a mixed Anhydride (isobutyl chloroformate through reaction). So that the intermediate is reacted with diazomethane to give The α-diazo ketones. In the presence of methanol to treatment with silver oxide to give the formula (XXXVII) with Department of esters.

11 formula (XXXIX) homologation of esters can also be prepared using the process described in 11.

Process 11

Step (yy)

In a suitable solvent, of the formula (XXIX) and (XXXXII) chloride with an alkyl malonate Ester (CH₃O ₂C) ₂CH ₂And bases. Typically, the base is an alkali metal alcoholate, such as sodium ethoxide Or potassium t-butoxide, the solvent is an alcohol, such as methanol or ethanol, or ethers, such as tetrahydrofuran Furans. Preferably, the selected base and the solvent, so that with the malonate reagent and the intermediate (XXXXIII) The transesterification minimized.

The method can be extended to substituted malonate (CH₃O ₂C) ₂CHR, wherein R is an alkyl group. This Obtained similar to (XXXIX) compounds wherein R is a group with R^AO ₂Group adjacent to the carbon C Atom substituents. These compounds can also be an alkali metal alcoholate in the presence of a base, The intermediate (XXXXIII) with R-Br or RI alkylation thereof.

Step (zz)

Then the intermediate (XXXXIII) decarboxylation to give the product (XXXIX). This can be through By using one equivalent of an alkali metal hydroxide (e.g., sodium hydroxide) selective hydrolysis, followed by Acidification, or any of the other methods known in the art achieved.

The following compounds other aspects of the present invention is constructed:

Formula (VII) compound

Where R⁵And R⁶Is as defined above.

Preferably the formula (VII^A) Compound

Where R⁵And R⁶Is as defined above.

Formula (VIII) Compound

Where R¹、R ²、R ⁵And R⁶Is as defined above.

Preferably the formula (VIII^A) Compound

Where R¹、R ²、R ⁵And R⁶Is as defined above.

By the following non-limiting examples further illustrate the present invention.

Melting point is used on a Gallenkamp melting point apparatus measuring glass capillary, and without school Positive. Unless otherwise indicated, all reactions are carried out under a nitrogen atmosphere and using a commercial Available on the anhydrous solvent. Carried out under microwave irradiation reaction is Emrys Creator Machine (Personal Chemistry Ltd.) Carried out using the power output 2.45GHz Out of 15 to 300W. "Ammonia 0.88" indicates a commercially available aqueous ammonia solution, specific gravity of about 0.88. TLC precoated glass back in the Merck silica gel (60F254) carried out on plates, silicon Gel column chromatography with 40-63μm silica gel (Merck silica gel 60) carried. Ion exchange chromatography With the specified ion exchange resin is carried out, the resin had pre-washed with deionized water. Proton NMR Spectra were Varian Inova 300, Varian Inova 400 or Varian Mercury 400 Spectrometer, in the solvents specified measurements. In the NMR spectrum, only the solvent peak is not reported With non-exchangeable protons. Low resolution mass spectrometry is used in thermal spray positive ionization Fisons Recorded on Trio 1000, or a positive or negative using electrospray ionization on a Finnigan Navigator on record. High resolution mass spectrometry using electrospray positive ionization is on a Bruker Apex II FT-MS recorded on. Combustion analysis is Exeter Analytical UK.Ltd., Uxbridge, Middlesex conducted. Polarimetry at 25 ℃, using PerkinElmer 341 The polarization was measured, using the specified solvent and concentration. Is named as (+) or (-) rotation Optical isomers Example compounds is based on the determination of a suitable solvent in the rotation signal to Named. ...

Arbocel ^TM	Filtering agent, from J.Rettenmaier & Sohne, Germany
Arbocel ^TM	Filtering agent, from J.Rettenmaier & Sohne, Germany	Amberlyst ^ 15	Ion exchange resins, can be obtained from Aldrich Chemical Company
APCI	Atmospheric pressure chemical ionization	Amberlyst ^ 15
APCI	Atmospheric pressure chemical ionization	atm	Atmospheric pressure (1atm = 760torr = 101.3kPa)
Biotage ^TM	Use from Biotage, UK's Flash 75 chromatography silica gel cartridge conducted	atm	Atmospheric pressure (1atm = 760torr = 101.3kPa)
Biotage ^TM		BOC	Tert-butoxycarbonyl
br	Broad	BOC	Tert-butoxycarbonyl

c	For optical measurement of the concentration in grams per 100ml in total (1mg/ml is c 0.10)
c		cat	Catalytic
d	Twin Peaks	cat	Catalytic
d	Twin Peaks	dd	Doublet of doublets
Degussa ^101	10wt% palladium on activated carbon, Degussa E101 type, available from Aldrich Chemical Company to obtain	dd	Doublet of doublets
Degussa ^101		Develosil	Manufactured by Phenomenex supply by Nomura Chemical Manufacturing
Combi-RP C ₃₀hplc column	By the spherical silica particles (size 3μm or 5μm) columns, Chemically bonded to a surface of C30 chains. These particles are packed in a stainless steel Steel columns, the inner diameter of 2cm, length 25cm	Develosil
Combi-RP C ₃₀hplc column		Dowex ^	Ion-exchange resins, from Aldrich Chemical Company
ee	Enantiomeric excess	Dowex ^	Ion-exchange resins, from Aldrich Chemical Company
ee	Enantiomeric excess	HRMS	High resolution mass spectrum (electrospray ionization positive scan)
Hyflo ^TM	Hyflo supercel ^From Aldrich Chemical Company	HRMS
Hyflo ^TM	Hyflo supercel ^From Aldrich Chemical Company	liq	Liquid
LRMS	Low resolution mass spectrometry (electrospray ionization or thermal spraying positive scan)	liq	Liquid
LRMS		LRMS(ES ^-)	Low resolution mass spectrometry (electrospray ionization negative scan)
m	Multiplet	LRMS(ES ^-)
m	Multiplet	m/z	Mass peak
MCI ^TMGel	Porous polymer CHP20P 75-150μm, from Mitsubishi Chemical Corporation	m/z	Mass peak
MCI ^TMGel		Phenomenex Luna C18hplc Column	Manufactured by Phenomenex supply, the spherical silica particles (size 5μm or 10μm), a C18 chain, chemically bonded to the surface. These particles Is packed in a stainless steel column, diameter 2.1cm, length 25cm
psi	Pounds per square inch (1psi = 6.9kPa)	Phenomenex Luna C18hplc Column
psi	Pounds per square inch (1psi = 6.9kPa)	q	Quartet
R _f	Retention factor on TLC	q	Quartet
R _f	Retention factor on TLC	s	Unimodal

Sep-Pak ^	Inverting C₁₈Silicone cartridges, Waters Corporation
Sep-Pak ^	Inverting C₁₈Silicone cartridges, Waters Corporation	t	Triplet
TLC	TLC	t	Triplet
TLC	TLC	δ	Chemical drift

Unless the contrary is suggested in this article:

PyBOP  represents benzotriazol-1 - yloxytris (pyrrolidino) phosphonium hexafluorophosphate;

PyBrOP  represents bromo three pyrrolidino phosphonium hexafluorophosphate;

CDI means N, N'-carbonyldiimidazole;

WSCDI means 1 - (3 - dimethylaminopropyl) -3 - ethylcarbodiimide hydrochloride;

Mukaiyama reagent is 2 - chloro-1 - methylpyridinium iodide;

DCC represents N, N'-dicyclohexyl carbodiimide;

HOAT is 1 - hydroxy-7 - aza-benzotriazole;

HOBT is 1 - hydroxybenzotriazole hydrate;

Hunig base means N-ethyl-diisopropylamine;

Et ₃N is triethylamine;

NMM means N-methylmorpholine;

NMP is 1 - methyl - 2 - pyrrolidone;

DMAP represents 4 - dimethylaminopyridine;

NMO represents a 4 - methylmorpholine N-oxide;

KHMDS means bis (trimethylsilyl) amide potassium;

NaHMDS represents bis (trimethylsilyl) amide sodium;

DIAD represents isopropyl azodicarboxylate;

DEAD expressed diethyl azodicarboxylate;

DIBAL represents diisobutyl aluminum hydride;

Dess-Martin periodinane means 1,1,1 - triacetoxy-1, 1 - dihydro- -1,2 - Benzo iodo Hetercyclopentene (benziodoxol) -3 (1H) - one;

TBDMS-Cl means tert-butyl dimethyl chlorosilane;

TMS-Cl means chlorotrimethylsilane;

BOC is t-butyloxycarbonyl;

CBz means benzyloxycarbonyl;

Expressed MeOH methanol;

EtOH represents ethanol;

EtOAc represents ethyl acetate;

THF represents tetrahydrofuran;

Dimethyl sulfoxide DMSO representation;

DCM represents methylene chloride;

DMF means N, N-dimethylformamide;

AcOH representation acid;

TFA represents trifluoroacetic acid.

The following Examples illustrate the formula (I) compounds.

Example 1-28

The required monochloride (see Preparation 68,70-82,85,86 and 90) (1eq), HNR required³R ⁴Amine (5eq) and N-ethyl diisopropylamine (5eq) in dimethylsulfoxide (3-4mL.mmol^-1) Solution at 120 ℃ heated in a sealed vessel for 18 hours. The reaction mixture Composition was diluted with water and the product extracted with ethyl acetate (x3). The combined organic layer was washed with water, Dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by silica gel column chromatography, with dichloromethane Methane: ethyl acetate, dichloromethane: methanol or pentane: ethyl acetate as an eluent.

With the above method the following compounds:

12	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃；R ^10A＝H；R ^10B＝-CH ₃ ¹H NMR(CDCl ₃，400MHz)δ：1.25(t，3H)，1.40(d，3H)，2.48(s，3H)，3.01 (m，2H)，3.17(m，1H)，3.26(m，2H)，3.66(q，2H)，3.91(t，2H)，4.63(m， 4H)，8.13(d，1H)，8.56(d，1H)，8.87(s，1H)，10.15(br s，1H).LRMS：m/z ES ₊：398，[MH] ⁺
12		13	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃；R ^10A＝-CH(CH ₃) ₂；R ^10B＝H ¹H NMR(CDCl ₃，400MHz)δ：1.12(m，1H)，1.18(m，6H)，1.26(t，3H)，2.10 (br m，1H)，2.47(s，3H)，3.04(m，2H)，3.44(m，2H)，3.67(m，2H)，3.91(t， 2H)，4.64(t，2H)，4.70-4.86(br m，2H)，8.14(d，1H)，8.54(d，1H)，8.88(s， 1H)，10.17(br s，1H).LRMS：m/z ES ₊：426，[MH] ⁺
4	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃；R ^10A＝H；R ^10B＝-CH(CH ₃) ₂ ¹H NMR(CDCl ₃，400MHz)δ：1.08(m，1H)，1.18(m，6H)，1.26(t，3H)，2.30 (m，1H)，2.47(s，3H)，3.10(m，2H)，3.25(m，2H)，3.67(m，2H)，3.91(t， 2H)，4.64(t，2H)，4.76(m，1H)，4.92(m，1H)，8.14(d，1H)，8.54(d，1H)， 8.88(s，1H)，10.20(br s，1H).LRMS：m/z ES ₊：426，[MH] ⁺	13
4		15	R ⁵＝-CH ₂CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃；R ^10A＝-CH ₃；R ^10B＝H ¹H NMR(CDCl ₃，400MHz)δ：1.26(t，3H)，1.30(d，3H)，1.39(t，3H)，2.78- 3.02(br m，7H)，3.66(q，2H)，3.91(t，2H)，4.62(m，4H)，8.15(d，1H)，8.55 (d，1H)，8.86(s，1H)，10.13(br s，1H).LRMS：m/z ES ₊：412，[MH] ⁺
16	R ⁵＝-CH ₂CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃；R ^10A＝H；R ^10B＝-CH ₃ ¹H NMR(CDCl ₃，400MHz)δ：1.26(t，3H)，1.30(d，3H)，1.39(t，3H)，2.78- 3.02(br m，7H)，3.66(q，2H)，3.91(t，2H)，4.62(m，4H)，8.15(d，1H)，8.55 (d，1H)，8.86(s，1H)，10.13(br s，1H).LRMS：m/z ES ₊：412，[MH] ⁺	15

17	R ⁵＝-CH ₂CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃；R ^10A＝-CH(CH ₃) ₂；R ^10B＝H ¹H NMR(CDCl ₃，400MHz)δ：1.21(d，6H)，1.27(t，3H)，1.39(t，3H)，2.30 (m，1H)，2.90(m，2H)，3.00(m，1H)，3.10(m，1H)，3.33(m，1H)，3.69 (m，4H)，3.93(t，2H)，4.66(t，2H)，4.84(m，2H)，8.14(d，1H)，8.62(d，1H)， 8.91(s，1H)，10.46(br s，1H).LRMS：m/z ES ₊：440，[MH] ⁺
17		18	R ⁵＝-CH ₂CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃；R ^10A＝H；R ^10B＝-CH(CH ₃) ₂ ¹H NMR(CDCl ₃，400MHz)δ：1.08(d，6H)，1.21(t，3H)，1.39(t，3H)，2.90 (m，4H)，3.11(m，2H)，3.21(m，2H)，3.63(m，2H)3.90(t，2H)，4.61(m， 3H)，4.78(br d，1H)，8.18(d，1H)，8.51(d，1H)，8.83(s，1H)，10.12(br s， 1H).LRMS：m/z ES ⁺：440，[MH] ⁺
19	R ⁵＝-CH ₂CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃；R ^10A＝-CH ₂CH ₃；R ^10B＝H ¹H NMR(CDCl ₃，400MHz)δ：1.16(t，3H)，1.25(m，5H)，1.39(t，3H)，2.91 (q，2H)，3.10(m，2H)，3.30(m，1H)，3.50(m，2H)，3.68(m，2H)，3.92(m， 2H)，4.65(t，2H)，4.77(m，2H)，8.06(d，1H)，8.55(d，1H)，8.88(s，1H)， 10.23(br s，1H).LRMS：m/z ES ⁺：426，[MH] ⁺	18
19		20 ^A	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂OCH(CH ₃) ₂；R ^10A＝-CH ₃；R ^10B＝H ¹H NMR(DMSO-d ₆，400MHz)δ：1.04(d，6H)，1.33(d，3H)，2.38(s，3H)， 3.08-3.11(m，2H)，3.30-3.40(m，3H)，3.59(m，1H)，3.75(t，2H)，4.55(d， 2H)，4.61(m，2H)，8.08(d，1H)，8.70(d，1H)，9.01(s，1H)，9.30(br 1H)，9.54 (br，1H).LRMS：m/z APCI ⁺412，[MH] ⁺
21 ^A	R ⁵＝H；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃；R ^10A＝-CH ₃；R ^10B＝H ¹H NMR(DMSO-d ₆，400MHz)δ：1.05(t，3H)，1.32(d，3H)，3.03(m，1H)， 3.14(m，1H)，3.35(m，3H)，3.47(q，2H)，3.79(t，2H)，4.50(m，2H)，4.73 (t，2H)，7.98(s，1H)，8.05(d，1H)，8.72(d，1H)，9.01(s，1H)，9.40(br s， 1H)，9.52(br s，1H).LRMS：m/z APCI ⁺384，[MH] ⁺	20 ^A

22	R ⁵＝-CH ₂CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃；R ^10A＝-CH ₃；R ^10B＝-CH ₃ ¹H NMR(CD ₃OD，400MHz)δ：1.18(d，6H)，1.22(t，3H)，1.36(t，3H)，2.53 (t，2H)，2.89(m，4H)，3.65(q，2H)，3.88(m，2H)，4.63(m，4H)，8.20(d， 1H)，8.57(d，1H)，8.79(s，1H).LRMS：m/z ES ⁺426，[MH] ⁺
22		23	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂O(CH ₂) ₂CH ₃；R ^10A＝-CH ₃；R ^10B＝H ¹H NMR(CD ³OD，400MHz)δ：0.76(t，3H)，1.19(d，3H)，1.63(m，2H)， 2.43(s，3H)，2.68(m，1H)，2.89(m，2H)，3.06(m，2H)，3.54(t，2H)，3.87(t， 2H)，4.59(m，2H)，4.65(t，2H)，8.20(d，1H)，8.58(d，1H)，8.79(s，1H). LRMS：m/z APCI ⁺412，[MH] ⁺
24	R ⁵＝-CH ₃；R ⁶＝-CH(CH ₃) ₂；R ^10A＝-CH ₃；R ^10B＝H ¹H NMR(CD ₃OD，400MHz)δ：1.18(d，3H)，1.47(dd，6H)，2.43(s，3H)， 2.64(m，1H)，2.87(m，2H)，3.06(m，2H)，4.50(br s，2H)，5.00(br，1H)， 7.88(br s，1H)，8.53(d，1H)，8.79(s，1H).LRMS：m/z APCI ⁺368，[MH] ⁺	23
24		25 ^A	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₃OCH ₂CH ₃；R ^10A＝-CH ₃；R ^10B＝H ¹H NMR(DMSO-d ₆，400MHz)δ：0.96(t，3H)，1.32(d，3H)，1.88(m，2H)， 2.41(s，3H)，2.94-3.20(br m，3H)，3.23-3.42(br m，6H)，4.44-4.59(br m， 4H)，7.81(d，1H)，8.62(d，1H)，8.95(s，1H).LRMS APCI m/z 412[MH] ⁺

A = the product was dissolved in methylene chloride, treated with ethereal HCl and then evaporated in vacuo, HCl salt obtained.

Example 1-28 annotations

Example 3: azetidin-3 - yl-carbamic acid tert-butyl ester as HNR³R ⁴Amines. Will be a sufficient amount of methylene chloride in the product was 9eq trifluoroacetic acid to effect dissolution, stirring for 18 Hours. The reaction mixture was concentrated in vacuo to give the compound as a trifluoroacetate salt.

Examples 13 and 17: Using the (2R) -2 - isopropyl-piperazine (WO 01/32646, pg.19, Description Example 54) as HNR³R ⁴Amines.

Examples 14 and 18: Using the (2S) -2 - isopropyl-piperazine (US 6432957, pg.29, Preparation Example 65) as HNR³R ⁴Amines.

Example 19: Using the (2R) -2 - ethyl-piperazine (prepared in Example 124) as the HNR³R ⁴Amines.

Examples 29-90

The required monochloride (see Preparation 60,66,67,69,83,84,86-89) (1eq) and N-ethyl diisopropylamine (5eq) in dimethylsulfoxide (3.5-4mL.mmol^-1The required monochloride (see Preparation 60,66,67,69,83,84,86-89) (1eq) and N-ethyl diisopropylamine (5eq) in dimethylsulfoxide (3.5-4mL.mmol...³R ⁴The required monochloride (see Preparation 60,66,67,69,83,84,86-89) (1eq) and N-ethyl diisopropylamine (5eq) in dimethylsulfoxide (3.5-4mL.mmol...

When deprotection of the amine, and the crude product was treated with trifluoroacetic acid: dichloromethane (20:80 To 50:50 volume ratio) process, and the reaction was stirred for 6 hours or dissolved in dichloromethane and the At room temperature was treated with HCl in ether for 18 hours. Then the solution was evaporated in vacuo, silicon- Gel column chromatography (using dichloromethane: methanol: 0.88 ammonia, as eluent), or after HPLC purification (using Phenomenex Luna C18 2 × 15cm 5μm column and 0.1% trifluoroacetic Acetic acid aqueous solution: acetonitrile gradient elution) to give the title compound as a trifluoroacetate salt (B).

A = the product was dissolved in dichloromethane and treated with ethereal HCl, the solution is evaporated in vacuo, Hydrochloride was obtained.

B = Separation trifluoroacetate.

Example 29-90 annotations

Example 30: using 3 - methyl-piperazine-1 - carboxylic acid tert-butyl ester as HNR³R ⁴Amines.

Example 33: Using 3,5 - dimethyl-piperazine-1 - carboxylic acid tert-butyl ester (WO 93/01181, pg.30, Preparation Example 76) as the HNR³R ⁴Amines.

Examples 34,79,83,86,87 and 88: Using piperazine-1 - carboxylic acid tert-butyl ester for The HNR³R ⁴Amines.

Example 37: using 3 - Amino-azetidine-1 - carboxylic acid tert-butyl ester (WO 01/47901, pg.136, Preparation Example 78) as the HNR³R ⁴Amines.

Example 38: using 3 - (methylamino) azetidin-1 - carboxylic acid tert-butyl ester as a HNR³R ⁴Amines, see Preparation Example 6.

Example 39: Using the (2S) -2 - methyl-piperazine HNR³R ⁴Amines.

Example 45: Using the (piperidin-4 - yl)-carbamic acid tert-butyl ester as HNR³R ⁴Amines.

Example 46: Using the [1,4] diazepine -1 - carboxylic acid tert-butyl ester as HNR³R ⁴Amines.

Example 48: using 4 - amino-piperidine-1 - carboxylic acid tert-butyl ester as HNR³R ⁴Amines.

Example 49: Using the (piperidin-3 - yl methyl)-carbamic acid tert-butyl ester as HNR³R ⁴Amines.

Example 50: Using N-(2 - aminoethyl)-N-methyl-carbamic acid tert-butyl ester as a HNR³R ⁴Amines.

Example 53: using 3 - (aminomethyl) -1 - methylpiperidine (J.Am.Chem.Soc., 94 (26),1972,9151 -9158) as the HNR³R ⁴Amines.

Example 54: 1 - methyl-3 - (methylamino) piperidine as HNR³R ⁴Amine, the Senate See Preparation 5.

Example 62: N-methyl-N-(2 - (methylamino) ethyl) carbamic acid tert-butyl ester (EP 0296811 as in Example 1, Step A) as the HNR³R ⁴Amines.

Example 64: Using the (3R) -3 - amino-pyrrolidine-1 - carboxylic acid tert-butyl ester as HNR³R ⁴Amines.

Example 65: Using the (3S) -3 - (aminomethyl) pyrrolidine-1 - carboxylic acid tert-butyl ester as a HNR³R ⁴Amines.

Example 66: using 8 - methyl-3 ,8 - diazabicyclo [3.2.1] octane (US 3951980, pg.3, Example 1) as the HNR³R ⁴Amines.

Example 67: 4 - (methylamino) piperidine-1 - carboxylic acid tert-butyl ester as HNR³R ⁴Amines.

Example 68: Using (3 - aza-bicyclo [3.1.0] hex-6 - yl)-carbamic acid tert-butyl ester (J.Chem.Soc Perkin 1,2000,1615) as HNR³R ⁴Amines.

Example 70: Using the (pyrrolidin-3 - yl)-carbamic acid tert-butyl ester as HNR³R ⁴Amines.

Example 73: Using 6 - methyl -3,6 - diazabicyclo [3.2.2] nonane (EP 0297858, pg.8, Example 4) as the HNR³R ⁴Amines.

Example 74: 4 - (aminomethyl) piperidine-1 - carboxylic acid tert-butyl ester as HNR³R ⁴Amines.

Example 75: Using the (3S) -3 - methyl-piperazine-1 - carboxylic acid tert-butyl ester as HNR³R ⁴Amines.

Example 76: N-methyl-N-(piperidin-4 - yl methyl)-carbamic acid tert-butyl ester (US 5442044, pg.37, Example 108) as the HNR³R ⁴Amines.

Example 91

N-[1 - methyl -5 - ((3R) -3 - methyl-piperazin-1 - yl) -3 - propyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] pyrimidin-4 - yl amine

Of N-ethyldiisopropylamine (625μL, 4.5mmol) and (2R) -2 - methyl-piperazine (450mg, 4.5mmol) was added to the compound prepared in Example 69-chloro (270mg, 0.89mmol) in dimethylsulfoxide (8mL) solution, and the reaction mixture was heated to 120 ℃ under nitrogen for 18 hours. The reaction mixture Compound diluted with ethyl acetate, washed with water (2 × 30mL), then with brine (30mL) was washed. There will be Organic solution was dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using Dichloromethane: methanol: ammonia, 100:0:0 to 95:5:0.5 to give the title compound 142mg.

¹H NMR(CD ₃OD，400MHz)δ：0.97(t，3H)，1.17(d，3H)，1.78(m，2H)，2.62-3.20 (m，7H)，4.15(s，3H)，4.51(m，2H)，7.99(br s，1H)，8.54(d，1H)，8.79(s，1H).

LRMS：m/z ES+368，[MH] ⁺

Examples 92-122

The appropriate HNR¹R ²Amine (50μmol) 1 - methyl - 2 - pyrrolidone (100μL) was added Into the appropriate dichloro compound (see Preparation Examples 52,55,56 and 59) (50μL) for 1 - Methyl-2 - pyrrolidinone (100μL) solution, followed by N-ethyldiisopropylamine (50μL). Will The reaction mixture under nitrogen at 90 ℃ for heating for 36 hours. The reaction mixture was cooled and added to appropriate When the HNR³R ⁴Amine (150μmol) in dimethylsulfoxide (125μL) solution, followed by more N- Ethyldiisopropylamine (50μL). The reaction mixture was heated at 120 ℃ for 72 hours and then cooled Cooling. The crude product was purified by HPLC on Phenomenex Luna C18 column, 5μm, 30 × 4.6mm id, in the 40 ℃ using acetonitrile: 0.05% ammonium acetate (aq.) (gradient of 90:10 to 5:95 After 2.20 minutes at a flow rate 3mL/min.

With the above method the following compounds:

Example 92-122 comments

Example 95: Using the (3S) -3 - methoxy-pyrrolidine as HNR³R ⁴Amines, see Preparation 7.

Example 101: using 3 - amino-propionic acid tert-butyl ester as HNR³R ⁴Amines.

Example 107: using 3 - amino-N-methyl-propionamide as HNR³R ⁴Amines, see Preparation Example 8.

Example 111: Using 2 - amino -5 - propoxy-pyridine (J.Med.Chem., 1981,24 (12),1518-1521) as the HNR¹R ²Amines.

Example 114: Using the (S) - (+) -2 - amino-1 - propanol as HNR³R ⁴Amines.

Example 115: Using 2 - (pyrazol-1 - yl) ethylamine (WO 02/066481, pg.60, Method 44) as HNR³R ⁴Amines.

Example 116: Using piperazine-1 - carboxylic acid tert-butyl ester as HNR³R ⁴Amines.

Example 117: Using (1S, 4S) -2,5 - diazabicyclo [2.2.1] heptane-2 - carboxylic acid Tert-butyl ester as HNR³R ⁴Amines.

Example 118: Using L-proline t-butyl ester as HNR³R ⁴Amines.

Example 119: Using N-(2 - aminoethyl)-N-methyl-carbamic acid tert-butyl ester as a HNR³R ⁴Amines.

Example 120: Using the (3S) -3 - (tert-butoxycarbonyl) pyrrolidine as HNR³R ⁴Amines.

Examples 123-130

Dichloride in Preparation Example 52 (1eq) in dimethylsulfoxide (1mL.mmol^-1) Was added The appropriate amine HNR¹R ²(2eq) in dimethylsulfoxide (0.75mL.mmol^-1) Solution. Join N-ethyl diisopropylamine (1eq), the reaction vessel was sealed with 140rpm at 80 ℃ oscillation 12 hours. The reaction mixture was then allowed to cool. Then the reaction mixture was added tert-piperazine Butyl acrylate or 33% solution of methylamine in ethanol (5eq) in dimethyl sulfoxide (0.66mL.mmol^-1) In Solution, followed by N-ethyldiisopropylamine (3eq), and the reaction vessel sealed and heated to 120 ℃, for 18 hours. The reaction mixture was evaporated to dryness. When you need to protect (Implementation Examples 123-129), adding dichloromethane (2.5mL.mmol^-1) And trifluoroacetic acid (2.5mL.mmol^-1), And the reaction mixture was sealed and stirred for 24 hours. Anti concentrated in vacuo Should be a mixture. The residue was Phenomenex Luna C18 2 × 15cm 5μm column purification, With acetonitrile: diethylamine to afford the title compound.

Examples 123-130 comments

Examples 123-129: Using piperazine-1 - carboxylic acid tert-butyl ester as HNR³R ⁴Amines.

Example 123: Using 2 - amino -5 - ethylpyridine as HNR¹R ²Amines, see Preparation 10.

Example 131

N-[1 - (2 - methoxy-ethyl) -5 - (piperazin-1 - yl) -3 - propyl-1H-pyrazolo [4.3-d] Pyrimidin-7 - yl] -4 - methyl-pyridin-2 - yl amine dihydrochloride

A mixture of 4 - methyl-pyridin-2 - yl amine (112mg, 1.037mmol) prepared in Example 65 was added to dichloro Compound (100mg, 0.346mmol) in dimethylsulfoxide (1mL) solution, and the reaction mixture was stirred at 70 ℃ stirred for 18 hours. Add piperazine-1 - carboxylic acid tert-butyl ester (322mg, 1.73mmol) And N-ethyl diisopropylamine (1mL), and the reaction mixture was stirred at 120 ℃ for 8 hours. Cold The reaction mixture was diluted with ethanol and ethyl acetate, and the organic phase was washed with water (2 × 15mL), Dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in dichloromethane (1mL), under nitrogen At room temperature was added trifluoroacetic acid (1mL). The reaction mixture was stirred at room temperature for 2 hours, Concentrated in vacuo. The residue was dissolved in dichloromethane (15mL), added 2M aqueous sodium bicarbonate until the The aqueous phase is alkaline. The organic phase was washed with water (10mL), dried over magnesium sulfate, concentrated in vacuo Shrink. The crude product was purified by column chromatography on silica gel, using ethyl acetate: methanol: diethylamine, 98:1:1 , To give a gum, which was dissolved in dichloromethane (2mL). 2M hydrogen chloride in ether solution added Solution (1mL), the mixture was dried, concentrated in vacuo to give a yellow solid 50mg. ...

¹H NMR(DMSO-d ₆，400MHz)δ：0.87(t，3H)，1.67(m，2H)，2.36(s，3H)，2.72(t， 2H)，3.20(m，4H)，3.24(s，3H)，3.71(m，2H)，3.89(m，4H)，4.65(m，2H)，7.05 (m，1H)，7.81(s，1H)，8.13(m，1H).LRMS：m/z ES+：411，[MH] ⁺

N-[1 - (2 - methoxy-ethyl) -5 - (piperazin-1 - yl) -3 - propyl-1H-pyrazolo [4,3-d] Pyrimidin-7 - yl] - (5 - methyl-2 - yl) amine dihydrochloride

Using 2 - amino-5 - methyl-pyridine as starting materials, by way of example 131 was prepared.

¹H NMR(DMSO-d ₆，400MHz)δ：0.87(t，3H)，1.66(m，2H)，2.25(s，3H)，2.73(t， 2H)，3.16(m，4H)，3.26(s，3H)，3.71(m，2H)，3.84(m，4H)，4.63(m，2H)，7.78 (m，1H)，7.91(m，1H)，8.12(s，1H).LRMS ES m/z 411[MH] ⁺

Examples 133-150

The appropriate homochiral amine (0.5mmol) ((2R, 5S) -2,5 - dimethyl-piperazin-1 - carboxylic acid Tert-butyl ester (WO 02/42292 Preparation Example 51) Preparation Example 3, or from a protected piperazine) (On the split, see WO 02/42292) in dimethyl sulfoxide (0.75mL) was added to a Appropriate monochloride (Preparation Example 72,74,117-123) (0.2mmol) in. Added N- Ethyl diisopropylamine (1mmol), the reaction vessel sealed and heated at 130 ℃ for 18 hours. The reaction mixture was concentrated in vacuo, the residue was treated with trifluoroacetic acid in methylene chloride (0.5mL/1.5mL) process, the solution was stirred at room temperature for 18 hours. Mixture was evaporated in vacuo Thereof. The residue was Phenomenex Luna C18 2 × 15cm 5μm column eluting with ethyl Nitrile: diethylamine to afford the title compound. ...

Preparation Example 56 using the dichloride, piperazine-1 - carboxylic acid tert-butyl ester and the appropriate HNR¹R ²Amine as starting materials, by way of example 131 the following compounds were prepared, but the free base The product was isolated form.

Example 153

3 - ethyl-1 - (2 - methoxyethyl)-N⁷- (4 - methyl-2 - yl)-N⁵- (2 - (pyrazol- -1 - Yl) ethyl)-1H-pyrazolo [4,3-d] pyrimidine -5,7 - diamine

A mixture of 2 - amino - 4 - methyl-pyridine (118mg, 1.09mmol) prepared in Example 56 was added to dichloro Compound (10mg, 0.36mmol) in dimethylsulfoxide (1mL) solution, and the reaction mixture was stirred at 70 ℃ stirred for 18 hours. 2 - (pyrazol-1 - yl) ethylamine (WO 02/066481, pg. 60, method 44) (202mg, 1.82mmol) and N-ethyldiisopropylamine (632μL, 3.64mmol), and the reaction mixture was stirred at 120 ℃ for 18 hours. The reaction mixture Partitioned between ethyl acetate and water, the organic phase separated, washed with water and brine, dried over magnesium sulfate Dry, concentrated in vacuo to give the title product.

¹H NMR(CD ₃OD，400MHz)δ：1.34(t，3H)，2.37(s，3H)，2.85(q，2H)，3.46(s， 3H)，3.84(m，4H)，4.40(t，2H)，4.63(br s，2H)，6.23(s，1H)，6.90(d，1H)，7.47(s， 1H)，7.53(s，1H)，8.12(d，1H)，8.23(s，1H).LRMS：m/z APCI+422，[MH] ⁺

Example 154

(2S) -2 - [3 - ethyl-1 - (2 - methoxyethyl) -7 - (4 - methyl-pyridin-2 - yl amino Yl)-1H-pyrazolo [4,3-d] pyrimidin-5 - yl amino] propan-1 - ol

Using (S) -2 - amino-propanol as starting materials, by way of example 153 was prepared.

¹H NMR(CD ₃OD，400MHz)δ：1.32(m，6H)，2.49(s，3H)，2.82(q，2H)，3.39(s， 3H)，3.65(dd，1H)，3.73(dd，1H)，3.87(t，2H)，4.16(m，1H)，4.86(t，2H)，7.10(d， 1H)，7.75(br s，1H)，8.12(d，1H).LRMS：m/z APCI+386，[MH] ⁺

Examples 155-162

A material with the appropriate chloride (Preparation Example 72,74,117,120,122 and 123) And HNR³R ⁴Amine (Preparation Example 114 and 115), by way of examples 1-28 was prepared under the Compounds of the formula shown, but first a Phenomenex C18 5μm column eluting with acetonitrile: Water: trifluoroacetic acid (5:95:0.95 to 95:5:0.05) as the eluent, followed by Phenomenex C18 5μm column eluting with acetonitrile: 50mM ammonium acetate gradient (5:95 to 95:5) To give the title compound.

Preparation Example 114 using pyrrolidine as HNR³R ⁴Amine Preparation Examples 155 to 160. Use Preparation Example 115 pyrrolidine as HNR³R ⁴Amine Preparation Examples 161 and 162.

Example 163

N-[3 - methyl-5 - (piperazin-1 - yl) -1 - (tetrahydropyran-2 - ylmethyl)-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -5 - methyl-pyridin-2 - yl amine dihydrochloride

Potassium carbonate (57mg, 0.33mmol) and 2 - (bromomethyl) tetrahydro-2H-pyran (50μL, 0.39mmol) prepared in Example 94 was added to the protected piperazine (150mg, 0.35mmol) in N, N- Dimethylformamide (10mL) solution, and the reaction mixture was stirred at 90 ℃ for 18 hours. The reaction mixture was partitioned between ethyl acetate (50mL) and water (50mL) was partitioned between organic phase was separated, Dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using pentane: 100:0 to 40:60 ethyl acetate as eluent. The product was dissolved in methylene chloride (10mL), pass into the chlorine Hydrogen, until saturation is reached, the reaction was stirred at room temperature for 3 hours. Solution was concentrated in vacuo, The product was triturated with ether, ether was decanted, the product was dried in vacuo. ...

¹H NMR(D ₂O，400MHz)δ：1.20-1.90(m，6H)，2.31(s，3H)，2.38(s，3H)，3.49 (m，4H)，3.50(m，1H)，3.76(m，1H)，4.00(m，4H)，4.18(m，1H)，4.50(m，2H)， 7.62(d，1H)，8.04(d，1H)，8.13(s，1H).LRMS：m/z APCI+423，[MH] ⁺

Potassium carbonate (59mg, 0.42mmol) and the appropriate R⁶Bromide (0.35mmol) was added to Example 97 Preparation of protected piperazine (150mg, 0.35mmol) in N, N-dimethylformamide (3mL) Solution, and the reaction mixture at 100 ℃ oscillation to 550rpm for 36 hours. In vacuo The reaction mixture was concentrated. The product was dissolved in dichloromethane (2mL), trifluoroacetic acid (2mL). The reaction mixture was shaken for 2 hours and concentrated in vacuo. The residue was Phenomenex Luna C18 2 × 15cm 5μm column eluting with acetonitrile: diethylamine to afford the title compound.

Examples 164-177 comments

Example 167 and 176: using 2 - (bromomethyl) pyridine (US 6465486, pg.12, solid Example 5) As R⁶Bromide.

Example 169: using 3 - (bromomethyl) tetrahydrofuran (WO99/45006, pg.117, the system Preparation Example 9) As R⁶Bromide.

Example 175: using 3 - bromo-tetrahydropyran (prepared in Example 125) as R⁶Bromide.

Example 178

N-[3 - isopropyl-1 - (2 - methoxy-ethyl) -5 - (piperazin-1 - yl)-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-pyridin-2 - yl amine bis (trifluoroacetate)

Preparation Example 92 from the BOC-protected compound (150mg, 0.3mmol) in dichloromethane Methane (5mL) and trifluoroacetic acid (5mL) was stirred at room temperature for 2 hours. Concentrated in vacuo The reaction mixture, the residue azeotroped with toluene. Product was purified by column chromatography on silica gel with diethyl Chloride: methanol (100:0 to 95:5) to give the title compound as a gum, 30mg.

¹H NMR(DMSO-d ₆，400MHz)δ：1.34(d，6H)，2.31(s，3H)，2.86(m，4H)，3.18 (m，1H)，3.35(s，3H)，3.62(m，4H)，3.74(m，2H)，4.58(m，2H)，6.90(s，1H)，7.99 (s，1H)，8.17(d，1H).LRMS：m/z APCI+411，[MH] ⁺

Example 179

N-[3 - isopropyl-1 - (2 - methoxy-ethyl) -5 - (piperazin-1 - yl)-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -5 - methyl-pyridin-2 - ylamine

Preparation Example 93 from the BOC-protected compound (150mg, 0.3mmol) in dichloromethane Methane (5mL) and trifluoroacetic acid (5mL) was stirred at room temperature for 2 hours. Concentrated in vacuo The reaction mixture, the residue azeotroped with toluene. Product was purified by column chromatography through silica gel, using ethyl Acetate: methanol: diethylamine elution (100:0:0 to 96:2:2) to give the title compound 14.5mg.

¹H NMR(DMSO-d ₆，400MHz)δ：1.34(d，6H)，2.26(s，3H)，2.95(s，4H)，3.18(m， 1H)，3.35(s，3H)，3.71(m，4H)，3.76(t，2H)，4.60(t，2H)，7.63(d，1H)，7.97(d， 1H)，8.16(s，1H).LRMS：m/z APCI+411，[MH] ⁺

Example 180

N-[3 - ethyl-1 - (2 - methoxy-ethyl) -5 - (piperazin-1 - yl)-1H-pyrazolo [4,3-d] Pyrimidin-7 - yl] -5 - methyl-2H-pyrazol-3 - yl amine

Preparation Example 95BOC-protected compound with a solution of hydrogen chloride in ether (8mL, 2M) Development 30 minutes. The resulting gum was washed with ether, dissolved in sodium hydroxide (1M), extracted with ethyl acetate Taking (2 × 10mL). Organic phases were combined, dried over magnesium sulfate, and concentrated in vacuo to give the products Thereof.

¹H NMR(DMSO-d ₆，400MHz)δ：1.25(t，3H)，2.20(s，3H)，2.72(m，6H)，3.30(s， 3H)，3.60(m，4H)，3.72(t，2H)，4.56(m，2H)，6.36(s，1H)，9.42(s，1H).

LRMS：m/z ES+：386，[MH] ⁺，

Example 181

[1 - (2 - ethoxyethyl) -5 - (N-ethyl-N-methyl-amino) -7 - (4 - methyl-2 - Ylamino)-1H-pyrazolo [4,3-d] pyrimidin-3 - yl] methanol

Of N-ethyl-diisopropylamine (1.3mL, 7.5mmol) and N-ethyl methylamine (642μL, 7.5mmol) was added to Preparation Example 106 monochloride (544mg, 1.5mmol) in dimethyl sulfoxide (4mL) solution, and the reaction mixture was stirred at 120 ℃ for 18 hours. The reaction mixture was Cooling, in dichloromethane (200mL) and water (50mL) partitioned between. The organic layer was washed with water (2 × 50mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, With dichloromethane: methanol 100:0 to 94:6 to afford the title product 525mg.

¹H NMR(CD ₃OD，400MHz)δ：1.10(t，3H)，1.22(t，3H)，2.39(s，3H)，3.21(s， 3H)，3.60(q，2H)，3.78(q，2H)，3.89(m，2H)，4.76(t，2H)，4.80(s，2H)，6.92(d， 1H)，8.15(d，1H)，8.19(s，1H).LRMS APCI+m/z 386[MH] ⁺

Example 182

[5 - dimethylamino-1 - (2 - ethoxyethyl) -7 - (4 - methyl-2 - ylamino)-1H- Pyrazolo [4,3-d] pyrimidin-3 - yl] methanol

Using dimethylamine as a starting material, with the method of Example 181, the title compound was prepared.

¹H NMR(CD ₃OD，400MHz)δ：1.10(t，3H)，2.38(s，3H)，3.23(s，6H)，3.58(q， 2H)，3.87(t，2H)，4.66(m，2H)，4.81(m，2H)，6.93(d，1H)，8.15(d，1H)，8.41(s， 1H)

Example 183

N-[1 - (2 - ethoxy-ethyl) -3 - methoxy-5 - (piperazin-1 - yl)-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-pyridin-2 - yl amine dihydrochloride

The compound of Preparation 111 (150mg, 0.35mmol) was added to 25% sodium methoxide in methanol Solution (350μL, 1.4mmol) of 1 - methyl - 2 - pyrrolidone (3.5mL) in the solution, and the The reaction mixture at room temperature for 15 minutes. The reaction mixture was treated with acetic acid (60μL) quenching, With N-ethyldiisopropylamine (174μL) process, the solution of 1 - methyl - 2 - pyrrolidone dilution To 9mL. This solution (3mL) with piperazine-1 - carboxylic acid tert-butyl ester (93mg, 0.5mmol) treatment, The reaction mixture was sealed and heated to 110 ℃ up to 12 hours. The reaction mixture was concentrated in vacuo Material, the crude product in methylene chloride (10mL) and water (10mL) partitioned between. The layers were separated, the The organic phase was dried over magnesium sulfate, and evaporated in vacuo. The product was dissolved in dichloromethane (2mL) with a three Trifluoroacetic acid (2mL) mixture for 1 hour. The reaction mixture was concentrated in vacuo, in the second Chloride and partitioned between aqueous sodium bicarbonate solution. The organic layer was concentrated in vacuo. The crude product Was subjected to silica gel column chromatography, eluting with ethyl acetate: methanol: dichloromethane 96:2:2 as eluent. Will Product was dissolved in ether, treated with 2M ethereal HCl, the solution was evaporated in vacuo to give the title product 53mg. ...

¹H NMR(D ₂O，400MHz)δ：0.95(t，3H)，2.45(s，3H)，3.30(m，4H)，3.35(s，3H)， 3.48(q，2H)，3.84(t，2H)，3.95(m，4H)，4.72(s，2H)，4.75(m，2H)，7.21(d，1H)， 7.55(s，1H)，8.10(d，1H).LRMS：m/z APCI+427，[MH] ⁺

N-[1 - (2 - ethoxy-ethyl) -3 - methoxy-methyl -5 - ((3R) - (3 - methyl-piperazin-1 - Yl))-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-pyridin-2 - yl amine dihydrochloride

Using (R) -2 - methylpiperazine using the method of Example 183 This compound was prepared.

¹H NMR(D ₂O，400MHz)δ：0.92(t，3H)，1.32(d，3H)，2.45(s，3H)，3.17(m，2H)， 3.35(s，3H)，3.40-3.50(m，5H)，3.87(m，2H)，4.46(m，2H)，4.68(s，2H)，4.73 (m，2H)，7.21(d，1H)，7.57(s，1H)，8.10(d，1H).LRMS：m/z APCI+441，[MH] ⁺

Example 185

1 - (2 - ethoxy-ethyl) -3 - methoxymethyl-N⁵，N ⁵- Dimethyl-N⁷- (4 - methyl-pyridine -2 - Yl)-1H-pyrazolo [4,3-d] pyrimidine -5,7 - diamine

Using N, N-dimethylamine, by way of example a method for preparing the compound 183. After heating, The reaction mixture was concentrated in vacuo, the crude product was purified by column chromatography on silica gel, eluting with dichloromethane: Methanol 98:2 to give the title product.

¹H NMR(CD ₃OD，400MHz)δ：1.11(t，3H)，2.39(s，3H)，3.24(s，6H)，3.44(s， 3H)，3.60(q，2H)，3.90(t，2H)，4.70(m，4H)，6.93(d，1H)，8.15(d，1H)，8.41(s， 1H).LRMS：m/z APCI+386，[MH] ⁺

Example 186

N-[1 - (2 - ethoxy-ethyl) -3 - ethoxy-5 - (piperazin-1 - yl)-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-pyridin-2 - yl amine dihydrochloride

Use a 21% ethanol solution of sodium ethoxide, method of Example 183 using the compound prepared in Thereof. The crude product was purified by column chromatography on silica gel with dichloromethane: methanol 100:0 to 94:6 Wash Off. Incorporate the appropriate section, concentrated in vacuo, dissolved in ether, washed with 2M solution of hydrogen chloride in ether Treatment. The reaction mixture was concentrated in vacuo to give the title product.

¹H NMR(D ₂O，400MHz)δ：0.88(t，3H)，1.08(t，3H)，2.39(s，3H)，3.26(m，4H)， 3.42(q，2H)，3.58(q，2H)，3.83(t，2H)，3.90(m，4H)，4.70(m，4H)，7.14(d，1H)， 7.50(s，1H)，8.04(d，1H).LRMS：m/z APCI+441，[MH] ⁺

Example 187

N-[1 - (2 - ethoxy-ethyl) -3 - ethoxy-methyl -5 - ((3R) - (3 - methyl-piperazin-1 - Yl))-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-pyridin-2 - yl amine dihydrochloride

Using 21% sodium ethoxide in ethanol and (R) -2 - methylpiperazine using Example 183 The method of preparing the compound.

¹H NMR(D ₂O，400MHz)δ：0.88(t，3H)，1.06(t，3H)，1.28(d，3H)，2.40(s，3H)， 3.12(m，2H)，3.30-3.50(m，5H)，3.55(q，2H)，3.82(t，2H)，4.42(m，2H)，4.73(m， 4H)，7.14(d，1H)，7.50(s，1H)，8.05(d，1H).LRMS：m/z APCI+455，[MH] ⁺

Example 188

1 - (2 - ethoxy-ethyl) -3 - ethoxy-methyl-N⁵，N ⁵- Dimethyl-N⁷- (4 - methyl-pyridine -2 - Yl)-1H-pyrazolo [4,3-d] pyrimidine -5,7 - diamine

Using 21% sodium ethoxide in ethanol and dimethylamine, using the method as in Example 183 Preparation of the compound.

¹H NMR(CD ₃OD，400MHz)δ：1.09(t，3H)，1.22(s，3H)，2.38(s，3H)，3.22(s， 6H)，3.57(q，2H)，3.64(q，2H)，3.87(t，2H)，4.68(t，2H)，4.72(s，2H)，6.93(d， 1H)，8.15(d，1H)，8.41(s，1H).LRMS：m/z APCI+400，[MH] ⁺

Example 189

N-[1 - (2 - ethoxy-ethyl) -3 - methoxy-methyl -5 - ((3R) -3 - methyl-piperazin-1 - Yl)-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] pyrimidin-4 - yl amine dihydrochloride

Using (R) -2 - methyl-piperazine-chloro compound prepared in Example 112 as a starting material, by means of solid The method of Example 183 This compound was prepared.

¹H NMR(CD ₃OD，400MHz)δ：1.22(m，6H)，2.64-3.17(br m，4H)，3.44(s，3H)， 3.67(q，2H)，3.78，4.35(2d，1H)，3.91(t，2H)，4.60(d，2H)，4.78(m，4H)，8.21(d， 1H)，8.60(d，1H)，8.83(s，1H).LRMS APCI+m/z 428[MH] ⁺

Example 190

N-[1 - (2 - ethoxy-ethyl) -3 - methoxy-5 - (piperazin-1 - yl)-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] pyrimidin-4 - yl amine dihydrochloride

Use piperazine-1 - carboxylic acid tert-butyl ester and preparation of Example 112 as a starting material monochloro compound, by The method of Example 183 to help prepare the compound.

¹H NMR(CD ₃OD，400MHz)δ：1.21(t，3H)，2.97(m，4H)，3.43(s，3H)，3.66(q， 2H)，3.81(m，4H)，3.94(t，2H)，4.83(m，4H)，8.20(d，1H)，8.59(d，1H)，8.80(s， 1H).LRMS APCI+m/z 414[MH] ⁺

Example 191

1 - (2 - ethoxyethyl)-N⁵3 - dimethyl-N⁵- [(3S) -1 - methyl-pyrrolidin-3 - Yl]-N⁷- Pyrimidin-4 - yl-1H-pyrazolo [4,3-d] pyrimidine -5,7 - diamine

Monochloride in Preparation Example 72 (115mg, 0.35mmol) and the amine from Preparation 115 (197mg, 1.73mmol) and N-ethyl diisopropylamine (0.3mL, 1.73mmol) in dimethyl merger Sulfoxide (4mL), and the reaction mixture was stirred at 120 ℃ for 16 hours. The cooled The reaction mixture was extracted with ethyl acetate (10mL) and water (10mL) was diluted. The organic phase was separated, the aqueous phase into the Further extracted with ethyl acetate (3 × 10mL). The combined organic solution was washed with water (3 × 15mL), Dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel with methylene : Methanol 99:1 to 85:15, to give a gum 21mg.

¹H NMR(CD ₃OD，400MHz)δ：1.20(t，3H)，2.01-2.28(m，2H)，2.42(s，3H)，2.48 (s，3H)，2.76(m，2H)，2.95(m，2H)，3.16(s，3H)，3.64(q，2H)，3.87(t，2H)，4.63 (t，2H)，5.32(m，1H)，8.31(d，1H)，8.59(d，1H)，8.79(s，1H).LRMS：m/z ES+： 412，[MH] ⁺

Example 192

1 - (2 - ethoxy-ethyl) -3 - ethyl-N⁵- Methyl-N⁷- (5 - methyl-2 - Yl)-N⁵- [(3S) -1 - methyl-pyrrolidin-3 - yl]-1H-pyrazolo [4,3-d] pyrimidine -5,7 - two Amine

Example 131 according to the method of Example 54 from the dichloro compound was prepared from the system Example 115 Preparation of the amine and 2 - amino -5 - methyl-pyridine The title compound was prepared.

¹H NMR(CDCl ₃，400MHz)δ：1.20(t，3H)，1.39(t，3H)，2.1-2.3(m，2H)，2.37(s， 3H)，2.54(s，3H)，2.91(m，2H)，2.80-3.25(m，4H)，3.20(s，3H)，3.61(m，2H)， 3.95(m，2H)，4.63(m，2H)，5.50(m，1H)，7.53(d，1H)，8.14(s，1H)，8.28(d，1H) 9.65(br s，1H).HRMS：m/z ES+：439.29，[MH] ⁺

Example 193

1 - (2 - ethoxy-ethyl) -3 - ethyl-N⁵- Methyl-N⁵- [(3S) -1 - methyl-pyrrolidin-3 - Yl]-N⁷- Pyrimidin-4 - yl-1H-pyrazolo [4,3-d] pyrimidine -5,7 - diamine

Example 131 according to the method of Example 54 from the dichloro compound was prepared from the system Amine Preparation Example 115 and 4 - amino-pyrimidine The title compound was prepared.

¹H NMR(CDCl ₃，400MHz)δ：1.26(t，3H)，1.39(t，3H)，2.20-2.40(m，2H)，2.68(s， 3H)，2.90(q，2H)，3.11(s，3H)，3.05-3.40(m，4H)，3.67(q，2H)，3.92(m，2H)， 4.64(m，2H)，5.46(m，1H)，8.28(d，1H)，8.60(d，1H)，8.88(s，1H).HRMS：m/z ES+：426.27，[MH] ⁺

Examples 194-215

The appropriate chloro compound (Preparation Example 72,120,134,137,139,142, 143,144,159 and 161) (1eq), the appropriate HNR³R ⁴Amine (3-5eq) and N-ethylenebis Isopropylamine (3-5eq) was dissolved in dimethyl sulfoxide (3.5-6.9mL.mmol^-1), In a sealed container The reaction mixture was stirred at 120 ℃ for 18 hours. The reaction mixture between water and dichloromethane Partitioned between organic phase was separated, the aqueous phase was washed with dichloromethane (x2). The combined organic phases were combined, Dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography eluting with methylene chloride Chloride: methanol: 0.880 ammonia, 98:2:0 to 90:10:1 to afford the title product.

A-reaction not heated in a sealed container.

B-use 1eq cesium fluoride instead of N-ethyl-diisopropylamine.

Using C-HNR³R ⁴Amine trifluoroacetate and 9eq N-ethyl diisopropylamine.

D-in NMP, under microwave irradiation at 180 ℃, the reaction was carried out for 40 minutes.

E-through from ether / pentane developed and the product was isolated.

F-added 1eq tetraethyl ammonium fluoride.

Example 204: Using N-methyl-3 - azetidine amine bis (trifluoroacetate), as JP 2002 255932, pg 5 above.

Example 205 and 215: see Preparation Example 170.

Example 206 and 210: Using (1S, 4S) -2 - methyl-2 ,5 - diazabicyclo [2.2.1] Heptane, as Chem.Heterocyclo.Compd (Eng.Trans) 36; 4; 2000; 429-431 above.

Example 209: Preparation of Example 115 using information from the (3S) -1 - methyl-3 - (methylamino) pyridine Pyrrolidine.

Examples 216-228

The appropriate monochloro compound (Preparation Example 72,110,135,136,138,140, 159 and 162) (1eq) and the appropriate HNR³R ⁴Amine (5-6eq) was dissolved in dimethyl sulfoxide (5-10mL.mmol^-1), Will be in a sealed reaction vessel was heated to 110-120 ℃ Up to 18 hours. The reaction mixture was diluted with ethyl acetate, washed with water (x2), the organic phase was Dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography eluting with methylene chloride Chloride: methanol: 0.880 ammonia 95:5:0.5 99:1:0.125 to elute, and then ether / pentane development, To give the desired product.

A-reaction was diluted with dichloromethane not ethyl acetate.

B-purified by HPLC, using 0.1aq trifluoroacetic acid and acetonitrile as the eluent.

C-isolated as the HCl salt.

D-To the reaction was added cesium fluoride 1eq.

Example 229

N-[5 - ((1S, 4S) -2,5 - diazabicyclo [2.2.1] hept-2 - yl) -1 - (2 - ethoxy- Ethyl) -3 - ethyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-pyridin-2 - yl amine salt Salt

Preparation of example 122 from the chloro compound (2.3g, 6.37mmol), (1S, 4S) - (-) -2,5 - diazabicyclo [2.2.1] heptane-2 - carboxylic acid tert-butyl ester (3.8g, 19.11mmol) and cesium fluoride (967mg, 6.37mmol) was dissolved in dimethyl sulfoxide (15mL), the The reaction mixture was heated to 110 ℃ for 18 hours. Cooling the reaction mixture, in 10% citric acid Solution and ethyl acetate (400mL) allocated between the layers were separated. The aqueous phase with ethyl acetate (200mL) Extract the combined organic solution was washed with water (200mL), brine (200mL), then dried acid Magnesium sulfate, and concentrated in vacuo. The residue was dissolved in dichloromethane (40mL) and trifluoroacetic acid (10mL), and the solution stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, the The residue in dichloromethane (100mL) and sodium carbonate solution (100mL) partitioned between. The organic solvent Was dried over magnesium sulfate, and evaporated in vacuo. The crude product was purified by column chromatography on silica gel with diethyl Chloride: methanol: 0.880 ammonia elution (97.5:2.5:0.25 to 95:5:0.5). Then production Was dissolved in methanol, 2N hydrochloric acid (1eq), the solution was evaporated in vacuo. The solid from acetic acid Isopropyl ester / ether and recrystallized to give the title compound as a pale yellow solid 1.15g. ...

¹H NMR(CD ₃OD，400MHz)δ：1.10(t，3H)，1.34(t，3H)，2.17(m，1H)，2.35 (m，1H)，2.53(s，3H)，2.91(q，2H)，3.52(m，2H)，3.59(m，2H)，3.90(t，2H)，3.98 (m，2H)，4.64(m，1H)，4.86(m，2H)，5.20(m，1H)，7.15(d，1H)，7.97(s，1H)，8.22 (m，1H)

Preparation of example 122 from the chloro compound (2.3g, 6.37mmol), (1S, 4S) - (-) -2,5 - diazabicyclo [2.2.1] heptane-2 - carboxylic acid tert-butyl ester (3.8g, 19.11mmol) and cesium fluoride (967mg, 6.37mmol) was dissolved in dimethyl sulfoxide (15mL), the The reaction mixture was heated to 110 ℃ for 18 hours. Cooling the reaction mixture, in 10% citric acid Solution and ethyl acetate (400mL) allocated between the layers were separated. The aqueous phase with ethyl acetate (200mL) Extract the combined organic solution was washed with water (200mL), brine (200mL), then dried acid Magnesium sulfate, and concentrated in vacuo. The residue was dissolved in dichloromethane (40mL) and trifluoroacetic acid (10mL), and the solution stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, the The residue in dichloromethane (100mL) and sodium carbonate solution (100mL) partitioned between. The organic solvent Was dried over magnesium sulfate, and evaporated in vacuo. The crude product was purified by column chromatography on silica gel with diethyl Chloride: methanol: 0.880 ammonia elution (97.5:2.5:0.25 to 95:5:0.5). Then production Was dissolved in methanol, 2N hydrochloric acid (1eq), the solution was evaporated in vacuo. The solid from acetic acid Isopropyl ester / ether and recrystallized to give the title compound as a pale yellow solid 1.15g. ...₂₂H ₃₀N ₈O；HCl；1.5H ₂O requires C, 54.37; H, 7.05; N, 23.06%.

Example 230

N-[5 - ((1S, 4S) -2,5 - diazabicyclo [2.2.1] hept-2 - yl) -3 - methoxymethyl -1 - (2 - ethyl-propoxy)-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-2 - Ylamine

The process described in Example 229, was prepared from Example 160 from the chloro compound and (1S, 4S) - (-) -2,5 - diazabicyclo [2.2.1] heptane-2 - carboxylic acid tert-butyl ester to give the title Compound was isolated as the free base form of the compound.

¹H NMR(CD ₃OD，400MHz)δ：0.71(t，3H)，1.53(m，2H)，1.92(m，1H)，2.10(m， 1H)，2.42(s，3H)，3.17(q，2H)，3.43(s，3H)，3.50(m，2H)，3.66(m，1H)，3.68(m， 1H)，3.89(m，2H)，4.02(s，1H)，4.69(m，2H)，4.74(m，2H)，4.95(s，1H)，6.94(d， 1H)，8.14(d，1H)，8.33(m，1H).LRMS：m/z ES+453[MH] ⁺

Example 231

N-{5 - ((1S, 4S) -2,5 - diazabicyclo [2.2.1] hept-2 - yl) -3 - methyl- -1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -4 - Methyl-pyridin-2 - ylamine

Preparation of Example 141 using a chlorine compound and (1S, 4S) - (-) -2,5 - diazabicyclo [2.2.1] heptane-2 - carboxylic acid tert-butyl ester in Example 230 using similar method as described in Preparation of title product.

¹H NMR(CD ₃OD，400MHz)δ：1.84(m，1H)，1.97(m，1H)，2.40(s，3H)，2.41(s， 3H)，3.06(q，2H)，3.58(m，1H)，3.70(m，1H)，3.82(s，1H)，4.00(q，2H)，4.06(t， 2H)，4.72(m，2H)，4.84(m，1H)，6.92(d，1H)，8.13(d，1H)，8.25(m，1H)

LRMS：m/z ES+463[MH] ⁺

Example 232

N-[5 - (3,8 - diazabicyclo [3.2.1] oct-3 - yl) -1 - (2 - ethoxy-ethyl) -3 - Methyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-pyridin-2 - ylamine

The process described in Example 231, was prepared from from the chloro compound of Example 120 and 3,8 - Diazabicyclo [3.2.1] octane-8 - carboxylic acid tert-butyl ester (Tet.Lett.43 (2002), 899-902) to give the title compound as a yellow foam.

¹H NMR(CD ₃OD，400MHz)δ：1.12(t，3H)，1.89(m，4H)，2.41(2xs，6H)，3.19(m， 2H)，3.60(q，2H)，3.75(m，2H)，3.86(t，2H)，4.36(m，2H)，4.65(t，2H)，6.92(d， 1H)，7.39(d，1H)，8.20(br s，1H).LRMS：m/z ES+423[MH] ⁺

Examples 233-238

The appropriate monochloro precursor (Preparation Example 120,134,139,140, and 143) (1eq), Appropriate HNR³R ⁴Amine (3eq) and N-ethyldiisopropylamine (3eq) was dissolved in dimethyl sulfoxide (3.80mL.mmol^-1), And the reaction mixture was placed ReactiVial^TM, Heated to 120 ℃ Up to 18 hours. The reaction mixture was diluted with water, extracted with ethyl acetate. The organic Phase was dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in dichloromethane (20-50mL.mmol^-1), Was treated with trifluoroacetic acid (4-20mL.mmol^-1) Process, and the mixture at room Stirred at ambient temperature for 5 hours. Then the mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate, Washed with 10% sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography eluting with dichloromethane: methanol 99:1 to 98:2 as eluent to give The desired product.

Example 239

N-[5 - (3,8 - diazabicyclo [3.2.1] oct-3 - yl) -3 - methyl-1 - (2 - ethyl-propoxy Yl)-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -6 - methyl-pyridin-2 - ylamine

In a sealed container, from the chloro compound of Preparation 171 (150mg, 0.42mmol), 3,8 - diazabicyclo [3.2.1] octane-8 - carboxylic acid tert-butyl ester (Tet.Lett. 43 (2002) ,899-902) (446mg, 2.1mmol) and cesium fluoride (63.8mg, 0.42mmol) In dimethyl sulfoxide (3mL) the mixture heated at 110 ℃ for 18 hours. The reaction was poured Into water, the resulting precipitate filtered off. The solid was dissolved in methylene chloride, the solution was evaporated in vacuo. The solid was re-dissolved in methylene chloride (6mL), trifluoroacetic acid (2mL), at room temperature, the solution Stirred for 3 hours. The mixture was concentrated in vacuo, and the residue between dichloromethane and 2N hydrochloric acid Allocated between the layers were separated. The aqueous solution was basified with solid sodium carbonate, and then extracted with dichloromethane Extracted (3x). These organic extracts were dried over magnesium sulfate, and evaporated in vacuo. The crude product After column chromatography on silica gel, eluting with dichloromethane: methanol: 0.88 ammonia, gradient elution (100:0:0 To 98:2:0.25) to give the title compound as a yellow solid 65mg. ...

¹H NMR(CD ₃OD，400MHz)δ：0.73(t，3H)，1.57(m，2H)，1.75-1.86(m，4H)，2.40 (s，3H)，2.44(s，3H)，3.11(m，2H)，3.48(t，2H)，3.60(m，2H)，3.84(t，2H)，4.27 (m，2H)，4.65(t，2H)，6.90(d，1H)，7.66(m，1H)，8.10(br d，1H).LRMS：m/z APCI+437[MH] ⁺

The appropriate protected amines (1eq) and trifluoroacetic acid (7.5-12.5mL.mmol^-1) Was added to Dichloromethane (15-42mL.mmol^-1), And the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the residue between dichloromethane and aqueous sodium bicarbonate solution Distribution, separated, and the aqueous phase washed with dichloromethane. The organic layer was dried over magnesium sulfate, the Concentrated in vacuo. The residue was subjected to silica gel column chromatography, eluting with dichloromethane: methanol: 0.880 Ammonia 100:0:0 to 90:10:1 to afford the desired product.

Example 244

N-[5 - ((1R, 4R) -2,5 - diazabicyclo [2.2.1] hept-2 - yl) -1 - (2 - ethoxy- Ethyl) -3 - methyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-pyridin-2 - ylamine

The preparation of the product of Example 168 is protected (62mg, 0.12mmol) was dissolved in ethanol (5mL), the Was treated with palladium hydroxide (10mg) and 2M hydrochloric acid (124μL, 0.25mmol) process. The reaction mixture Compounds released into 60psi for 18 hours and then treated with additional catalyst (20mg) treatment, placed 60psi issued 18 hours. The reaction mixture was filtered through Arbocel , concentrated in vacuo The filtrate was. The residue was subjected to silica gel column chromatography, eluting with dichloromethane: methanol: 0.880 ammonia 95:5:0.5 to 90:10:1 to afford the title product 16mg.

¹H NMR(CD ₃OD，400MHz)δ：1.11(t，3H)，1.92(m，1H)，2.11(m，1H)，2.41(2xs， 6H)，3.21(m，2H)，3.58(m，2H)，3.70(q，2H)，3.84(m，2H)，4.09(s，1H)，4.65 (m，2H)，4.95(s，1H)，6.95(m，1H)，8.16(d，1H)，8.36(m，1H).LRMS：m/z APCI+409[MH] ⁺

Examples 245-257

The appropriate chloro compound (Preparation Example 191 至 202) (1eq) and the appropriate HNR³R ⁴Amine (3-5eq) was dissolved in dimethyl sulfoxide (2.7-13.6mL.mmol^-1), In a sealed container will The reaction mixture was stirred at 120 ℃ for 18 hours. The reaction mixture of water and ethyl acetate Distributed among the layers were separated. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. Residue After column chromatography on silica gel eluting with dichloromethane: methanol: 0.88 ammonia to afford the title product.

Preparation Example A-115 using information from the amine hydrochloride was added to the reaction an equimolar amount of N-ethyl diisopropylamine.

B-no in a sealed reaction vessel.

The product was purified by C-ethereal HCl to give the hydrochloride salt.

D-To the reaction mixture was added cesium fluoride 1eq.

Example 258

N-{3 - methyl-5 - piperazin-1 - yl-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazol Triazolo [4,3-d] pyrimidin-7 - yl} -6 - methyl-pyridin-2 - ylamine

Example 140 was prepared from the chloride (200mg, 0.5mmol), 1 - carboxylic acid tert-butyl piperazine Yl ester (165mg, 0.89mmol), cesium fluoride (76mg, 0.5mmol) and N-ethyl-diisopropylamine (0.88mL, 5.0mmol) in dimethyl sulfoxide (2mL) The mixture was stirred at 110 ℃ 18 Hours. The cooled mixture was partitioned between ethyl acetate (25mL) and water (25mL) was partitioned between points From the layers, the organic phase was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. Will be produced Was dissolved in dichloromethane (9mL), trifluoroacetic acid (3mL), stirred for 1.5 hours. In a vacuum The reaction was evaporated, and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate. Minute From the layers, the organic phase was dried over magnesium sulfate, and evaporated in vacuo. The residue was washed with ether / pentane Development, to give the title compound as an off-white solid, 117mg. ...

¹H NMR(CD ₃OD，400MHz)δ：2.40(s，3H)，2.46(s，3H)，2.93(m，4H)，3.75(m， 4H)，4.05(m，4H)，4.73(t，2H)，6.94(d，1H)，7.68(dd，1H)，8.05(m，1H).

LRMS：m/z APCI+451[MH] ⁺

N-{5 - (3,8 - diazabicyclo [3.2.1] oct-3 - yl) -3 - methoxymethyl -1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -4 - Methyl-pyridin-2 - ylamine

In the Reactivial , from the chloro compound of Preparation 193 (150mg, 0.35mmol), 3,8 - diazabicyclo [3.2.1] octane-8 - carboxylic acid tert-butyl ester (J.Med. Chem.1998, 41,674) (160mg, 0.72mmol) and N-ethyldiisopropylamine (244μL, 1.4mmol) in dimethyl sulfoxide (3mL) the mixture heated at 120 ℃ for 18 hours. Will Mixture was poured into water and extracted with dichloromethane (x2). The combined organic fractions were washed with water, Dried over magnesium sulfate, and evaporated in vacuo. The residual oil was dissolved in methylene chloride (6mL), added Trifluoroacetic acid (2mL), and the solution was stirred at room temperature for 3 hours. Reaction was concentrated in vacuo, And the residue partitioned between dichloromethane and 2N hydrochloric acid, the layers were separated. The aqueous phase is washed with methylene Alkyl washed and then basified with solid sodium bicarbonate. The solution was extracted with dichloromethane (3x), These organic extracts were combined, dried over magnesium sulfate, and evaporated in vacuo. The crude product through silica Gel column chromatography eluting with dichloromethane: methanol: 0.88 ammonia, gradient elution (98:2:0.25 to 96:4:0.5) to give the title compound as a yellow foam, 80mg. ...

¹H NMR(CD ₃OD，400MHz)δ：1.76-1.84(m，4H)，2.39(s，3H)，3.15(m，2H)，3.42 (s，3H)，3.59(m，2H)，4.02(q，2H)，4.10(t，2H)，4.28(m，2H)，4.68(s，2H)，4.77 (t，2H)，6.92(m，1H)，8.13(m，2H).LRMS：m/z APCI+507[MH] ⁺

N-{5 - [(1S, 4S) -2,5 - diazabicyclo [2.2.1] hept-2 - yl] -1 - (2 - ethoxy- Ethyl) -3 - methoxy-methyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -4 - methyl-2 - Ylamine

Following similar to that described in Example 259 The process of Example 159 was prepared from the chloride from And (1S, 4S) - (-) -2,5 - diazabicyclo [2.2.1] heptane-2 - carboxylic acid tert-butyl ester obtained standard Title compound as a yellow solid, but the product was not purified by column chromatography.

¹H NMR(CD ₃OD，400MHz)δ：1.11(t，3H)，2.01(m，2H)，2.42(s，3H)，3.32(m， 2H)，3.43(s，3H)，3.60(q，2H)，3.82(m，2H)，3.90(t，2H)，4.37(m，1H)，4.70(s， 2H)，4.74(m，2H)，5.06(m，1H)，6.97(d，1H)，8.17(d，1H)，8.32(s，1H).

LRMS：m/z APCI+439[MH] ⁺

Example 261

1 - {3 - methyl-7 - (4 - methyl-pyridin-2 - yl-amino) -1 - [2 - (2,2,2 - trifluoroethoxy) Ethyl]-1H-pyrazolo [4,3-d] pyrimidin-5 - yl} piperidin-4 - carboxylic acid

Sodium hydroxide solution (760μL, 1M, 0.76mmol) was added to Preparation Example 203 from Compound (200mg, 0.38mmol) in dioxane (5mL) solution, and the reaction was incubated at room temperature For 18 hours. The mixture was partitioned between ethyl acetate (20mL) and water (20mL) was partitioned between separation Layers. The aqueous phase was acidified with 1M citric acid solution, and then extracted with dichloromethane (2 × 50mL). These organic extracts were combined, dried over magnesium sulfate, and evaporated in vacuo. Residue was subjected to anti- Phase silica gel column chromatography, water: methanol gradient (100:0 to 20:80), in a vacuum Concentrating the appropriate section. The residue was dissolved in dichloromethane (10mL), the solution was dried over magnesium sulfate Dry, evaporate in vacuo to give the title compound 30mg. ...

¹H NMR(DMSO-d ₆，400MHz)δ：1.52(m，2H)，1.84(m，2H)，2.30(s，3H)，2.50 (m，4H)，3.00(m，2H)，3.95(t，2H)，4.06(q，2H)，4.47(m，2H)，4.64(m，2H)，6.78 (d，1H)，7.94(m，1H)，8.14(d，1H).LRMS：m/z ES-492[M-H] ^-

1 - {3 - methyl-7 - (6 - methyl-4 - ylamino) -1 - [2 - (2,2,2 - trifluoroethoxy) Ethyl]-1H-pyrazolo [4,3-d] pyrimidin-5 - yl} piperidin-4 - carboxylic acid

From the chloro compound of Preparation 197 (150mg, 0.37mmol) and iso-piperidine carboxylic acid Ethyl (ethyl isonipecotate) (188μL, 1.22mmol) in dimethyl sulfoxide (2mL) The mixture was heated at 120 ℃ for 3 hours. The mixture was cooled in dichloromethane (50mL) and water (50mL) was partitioned between the phases were separated. The organic layer was washed with water (2 × 25mL), Dried over magnesium sulfate, and evaporated in vacuo. The residue was dissolved in dioxane (2mL), hydroxide was added Sodium chloride (2.0mL, 1M, 2.0mmol), and the solution was stirred at room temperature for 18 hours. In vacuo Reaction was evaporated, and the residue in dichloromethane (20mL) and water (20mL) was partitioned between separation Layers, the aqueous layer was acidified with 1M citric acid. The solution was extracted into dichloromethane (2 × 50mL), The organic extracts were combined, dried over magnesium sulfate, and evaporated in vacuo. The crude product was subjected to silica gel column Chromatography, eluting with dichloromethane: methanol: acetic acid gradient elution (100:0:0 to 94:6:0.6), To give the title compound as a yellow solid, 87mg. ...

¹H NMR(CD ₃OD，400MHz)δ：1.73(m，2H)，2.02(m，2H)，2.44(s，3H)，2.50(s， 3H)，2.64(m，1H)，3.18(m，2H)，4.00-4.06(m，4H)，4.64(m，2H)，4.72(t，2H)， 8.17(m，1H)，8.64(s，1H).LRMS：m/z APCI+495[MH] ⁺

1 - {3 - ethyl-7 - (6 - methyl-4 - ylamino) -1 - [2 - (2,2,2 - trifluoroethoxy) Ethyl]-1H-pyrazolo [4,3-d] pyrimidin-5 - yl} piperidin-4 - carboxylic acid

In Reactivial  in Preparation Example 200, from the chloro compound (150mg, 0.36mmol) and isonipecotic Ethyl (277μL, 1.80mmol) in dimethyl sulfoxide (1.5mL) The mixture was heated at 120 ℃ for 18 hours. The cooled mixture was partitioned between ethyl acetate (50mL) and water (50mL) was partitioned between the phases were separated. The organic layer is washed with water (50mL) was washed Dried over magnesium sulfate, and evaporated in vacuo. The residue was dissolved in dioxane (3mL), hydroxide was added Sodium chloride (2.5mL, 1M, 2.5mmol), and the solution was stirred at room temperature for 72 hours. In vacuo Reaction was evaporated, the residue was dissolved in water (2mL), and the solution was acidified with 10% citric acid solution. The resulting precipitate was filtered off, washed with water, dried in vacuo at 45 ℃, to give the title compound as Yellow solid, 106mg. ...

¹H NMR(CD ₃OD，400MHz)δ：1.35(t，3H)，1.73(m，2H)，1.99(m，2H)，2.50(s， 3H)，2.62(m，1H)，2.89(q，2H)，3.15(m，2H)，3.96-4.09(m，4H)，4.60(m，2H)， 4.70(m，2H)，8.17(m，1H)，8.66(s，1H).LRMS：m/z APCI ₊509[MH] ⁺

Preparation Example 1

5 - isopropyl-4 - nitro-2H-pyrazole-3 - carboxamide

5 - isopropyl-4 - nitro-2H-pyrazole-3 - carboxylic acid (Farmaco, 46,11,1991, 1337-1350) (6g, 0.03mol) in N, N-dimethylformamide (69μL) and methylene chloride (67mL) solution in an ice / acetone cooled to -5 ℃. After 30 minutes added oxalyl chloride (11.48g, 0.09mol), and the reaction mixture was stirred for 1 hour, then the reaction mixture was warmed to room temperature 2 hours. The reaction mixture was concentrated in vacuo, the residual solvent is azeotroped with methylene chloride. The resulting solid was suspended in tetrahydrofuran (70mL), cooled to 0 ℃, adding 0.880 ammonia (25mL). The reaction mixture was stirred for 30 minutes and then concentrated in vacuo. The resulting solid Was suspended in water, filtered, dried under vacuum at 70 ℃, to give the product. ...

¹H NMR(DMSO-d ₆，400MHz)δ：1.28(d，6H)，3.55(m，1H)，7.59(s，1H)，7.89(s， 1H)，13.72(br s，1H).LRMS：m/z ES+199[MH] ⁺

4 - nitro-2H-pyrazole-3 - carboxamide

4 - nitro-2H-pyrazole-3 - carboxamide...

LRMS ES+m/z 157[MH] ⁺

4 - nitro-2H-pyrazole-3 - carboxamide...

Trans -2,5 - dimethyl-piperazine-1 - carboxylic acid tert-butyl ester

Of trans -2,5 - dimethyl-piperazine (10g, 0.087mol) was dissolved in dioxane (18mL) and water (8mL), cooled in an ice bath. Di-tert-butyl dicarbonate (19.29g, 0.089mol), the The reaction mixture was warmed to room temperature. Adding additional in dioxane (9mL) and water (4mL), the mixture Was stirred for 18 hours. In dioxane was removed in vacuo, the mixture was basified to pH 9, extracted Into ethyl acetate, dried over magnesium sulfate, and concentrated. Mixture was purified by column chromatography on silica gel, With methanol: dichloromethane 20:80 as eluent. The crude product was dissolved in ether, hydrochloric acid (0.5eq), The HCl salt of the title compound (2.73g).

¹H NMR(DMSO-d ₆400MHz)δ：1.21(2xd，6H)，1.40(s 9H)，2.90(dd，1H)，3.21 (dd 1H)，3.52(m 2H)，3.62(dd 1H)，4.25(m 1H)，9.2(br m 2H).LRMS：ES+m/z 215[MH] ⁺

Preparation Example 4

(3S) -3 - methyl-piperazine-1 - carboxylic acid tert-butyl ester

The (2S) -2 - methyl-piperazine (3.8g, 38mmol) and N-(t-butoxycarbonyl-oxy) phthalimide Phthalimide (10g, 38mmol) in dichloromethane (100mL) was stirred at room temperature for 3 Time. The mixture was washed with 2N sodium hydroxide solution, the organic solution was dried over magnesium sulfate, the true Air concentrated to give the title compound as a clear oil, 4.31g.

¹H NMR(CDCl ₃400MHz)δ：1.12(m，3H)，1.45(s，9H)，2.74-2.90(br m，3H)， 3.00(d，2H)，3.78(m，1H)，3.88-3.98(br m，2H).LRMS ES+m/z 201[MH] ⁺

Preparation Example 5

3 - (methylaminomethyl) -1 - methylpiperidine

In a sealed container, 3 - (chloromethyl) -1 - methyl-piperidine (9.2g, 50mmol) (US 6,184,338, Example 5) and 33% methylamine in ethanol (60mL) in ethanol (30mL) in the Solution was heated at 100 ℃ for 17 hours. The reaction mixture was concentrated in vacuo, diluted with water, Then extracted into methylene chloride, dried over magnesium sulfate. The reaction mixture was filtered in vacuo Concentrated to give the title product 8.2g.

Microanalysis: found C, 44.80%, H, 9.37, N, 13.21%.

C ₈H ₁₈N ₂Calcd C, 44.65%, H, 9.37%, N, 13.02%.

Preparation Example 6

3 - (methylamino) azetidin-1 - carboxylic acid tert-butyl ester

3 - iodo-azetidin-1 - carboxylic acid tert-butyl ester (EP 1176142, pg.23, implemented Example 2 (i)) (2.0g, 7.07mmol) was added to 33% solution of methylamine in ethanol (45mL), in the The reaction mixture was sealed container was heated at 100 ℃ for 24 hours. Anti concentrated in vacuo Should mixture of ethyl acetate and the residue partitioned between 1M aqueous sodium hydroxide solution. Separate The organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The crude product through silica Gel column chromatography eluting with dichloromethane: methanol: 0.880 ammonia 96:3.5:0.5 eluent to give the Title product.

¹H NMR(CDCl ₃，400MHz)δ：1.43(s，9H)，1.94(m，1H)，2.41(s，3H)，3.49(m， 1H)，3.67(m，2H)，4.06(m，2H).LRMS APC+m/z 187[MH] ⁺

Preparation Example 7

(3R) -3 - methoxy-pyrrolidine trifluoroacetate

The (3R) -3 - hydroxy-pyrrolidine-1 - carboxylic acid tert-butyl ester (25g, 133.4mmol) was dissolved in four Tetrahydrofuran (668mL), and the reaction mixture was cooled on an ice bath to 0 ℃. The reaction mixture was diluted with Sodium hydride (4.40g, 80% dispersion in mineral oil, 146.6mmol), stirred until the recovery room Temperature. Then, the reaction mixture was treated with methyl iodide (29.0g, 200.0mmol) treatment, at room temperature For 18 hours. The reaction mixture was washed with water (200mL) was diluted and concentrated in vacuo until Only the remaining aqueous components. The reaction mixture was diluted with ethyl acetate (1500mL) treatment, the organic Layers were dried over magnesium sulfate, and concentrated in vacuo to give the title product as a brown oil.

The oil (24.75g, 123.0mmol) was dissolved in diethyl ether (615mL), at room temperature to the Solution of hydrogen chloride up to one hour. The reaction mixture was concentrated in vacuo, redissolved in ether, Stirred for an additional 2 hours. Ether decanted off, the reaction mixture was concentrated in vacuo. The crude product was dissolved In ethanol, treated with trifluoroacetic acid (200mL) treatment, followed by stirring at room temperature for 2 hours. Concentrated in vacuo The reaction mixture was reduced to give the title product.

1H NMR(CD ₃OD，400MHz)δ：1.96(m，1H)，2.09(m，1H)，3.08-3.37(m，4H)， 4.06(m，1H)，4.80(s，3H).

Preparation Example 8

3 - amino-N-methyl-propionamide hydrochloride

The (2 - (methyl-carbamoyl)-ethyl) carbamic acid benzyl ester (7.92g, 33.52mmol) And 5% Pd / C (800mg) was dissolved in ethanol (300mL), and the reaction mixture at room temperature and 50psi Stirred for 4 hours under hydrogen. The reaction mixture was filtered through Arbocel , washed with ethanol, To the filtrate was added 1M hydrochloric acid solution (37mL). The reaction mixture was concentrated in vacuo, the crude product Azeotroped with dichloromethane (x3), dried in vacuo to give the title product 4.66g.

¹H NMR(CDCl ₃，400MHz)δ：2.48(m，2H)，2.61(s，3H)，2.97(m，2H)，7.89-8.11 (br m，3H)

Preparation Example 9

5 - vinyl-pyridin-2 - amine

Vinyl tributyltin (13mL, 44.6mmol), palladium acetate (II) (0.45g, 2.1mmol), triethylamine (12.4mL, 89.1mmol) and tri (o - tolyl) phosphine (3.69g, 12.15mmol) was added to 5 - bromo-2 - amine (7.0g, 40.5mmol) in acetonitrile (70mL) was dissolved Solution, the reaction mixture was refluxed for 18 hours. The reaction mixture was washed with 2M sodium carbonate solution (80mL) Washing the organic phase separated, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product was Column chromatography on silica gel eluting with methanol: dichloromethane 3:97, to give 3.6g product. Will The product was dissolved in methylene chloride, with aqueous potassium fluoride solution, and then washed with sodium bicarbonate. There will be Organic solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give 1.9g end product. ...

¹H NMR(400MHz，CDCl ₃)δ：4.52(br s，2H)，5.13(d，1H)，5.58(d，1H)，6.48(d， 1H)，6.57(m，1H)，7.54(d，1H)，8.05(s，1H).LRMS APCI+m/z 121[MH] ⁺

5 - ethyl-pyridin-2 - amine

A 10% palladium on carbon (300mg) was added to the amine prepared in Example 9 (1.7g, 14.1mmol) in ethanol (80mL) solution, and the reaction mixture was stirred under hydrogen at 15psi for 18 hours. The reaction mixture Was filtered through Arbocel , the filtrate was concentrated in vacuo. The resulting oil was dissolved in methylene chloride, Washed with a solution of potassium fluoride (2 × 10mL), and the organic phase was dried over magnesium sulfate, filtered, and the true Air concentrated to give 650mg product.

¹H NMR(400MHz，CDCl ₃)δ：1.16(t，3H)，2.48(q，2H)，4.35(br s，2H)，6.46(d， 1H)，7.26(m，1H)，7.89(m，1H)

Raw material

Use the following pyrazole as a raw material:

5 - methyl - 4 - nitro-2H-pyrazole-3 - carboxamide (US 4,282,361, Example 7)

5 - ethyl - 4 - nitro-2H-pyrazole-3 - carboxamide (WO 02/10171, pg.17, Preparation Example A synthetic j.)

4 - nitro-5 - propyl-2H-pyrazole-3 - carboxamide (WO 02/10171, pg.17, Preparation Example A synthetic k.)

5 - isopropyl-4 - nitro-2H-pyrazole-3 - carboxamide - see Preparation Example 1

4 - nitro-2H-pyrazole-3 - carboxamide - see Preparation Example 2

Preparation Example 11 to 23

Potassium carbonate (1eq) and the appropriate R⁶Br (1eq) was added to the appropriate pyrazole (see Materials) (1eq) in N, N-dimethylformamide (2-3mL.mmol^-1) Was added, and the reaction mixture was nitrogen Atmosphere and stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, partitioned between ethyl acetate and Partitioned between water and the organic phase was dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by silica gel Column chromatography eluting with ethyl acetate: pentane 50:50 to 100:0, to give the desired product.

17	R ⁵＝-CH(CH ₃) ₂；R ⁶＝-(CH ₂) ₂OCH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：1.26(d，6H)，3.18(s，3H)，3.42(m， 1H)，3.65(t，2H)，4.25(t，2H)，8.17(br s，1H)，8.40(br s，1H). LRMS：m/z ES+279[MNa] ⁺
17		18	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂O(CH ₂) ₂CH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：0.79(t，3H)，1.44(m，2H)，2.41(s， 3H)，3.29(t，2H)，3.70(t，2H)，4.22(t，2H)，8.18(s，1H)，8.33(s，1H). LRMS m/z APCI+257[MH] ⁺
19	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₃OCH ₂CH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：1.08(t，3H)，1.96(m，2H)，2.55(s， 3H)，3.32(m，2H)，3.37(m，2H)，4.15(t，2H)，7.64(br s，1H)，7.89(br s，1H).	18
19		20	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂OCH(CH ₃) ₂ ¹H NMR(CDCl ₃400MHz)δ：1.07(d，6H)，2.54(s，3H)3.56(m，1H)， 3.81(t，2H)，4.42(t，2H)，5.97(br s，1H)，7.54(br s，1H).LRMS APCI+m/z 257[MH] ⁺
21	R ⁵＝-(CH ₂) ₂CH ₃；R ⁶＝-(CH ₂) ₂OCH ₃ ¹H NMR(CDCl ₃，400MHz)δ：1.00(t，3H)，1.74(m，2H)，2.89(t，2H)， 3.33(s，3H)，3.78(t，2H)，4.49(t，2H)，5.95(br s，1H)，7.25(br s，1H). MS ES+m/z257[MH] ⁺	20
21		22	R ⁵＝-(CH ₂) ₂CH ₃；R ⁶＝-CH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：0.93(t，3H)，1.62(m，2H)，2.46(m， 2H)，3.78(s，3H)，8.08(m，1H)，8.32(m，1H).LRMS APCI m/z 213 [MH] ⁺

23	R ⁵＝-CH ₃；R ⁶＝-CH(CH ₃) ₂ ¹H NMR(DMSO-d ₆，400MHz)δ：1.38(d，6H)，2.42(s，3H)，4.45(m， 1H)，8.21(s，1H)，8.43(s，1H).LRMS：m/z APCI+213[MH] ⁺

Preparation Example 18 - using 1 - (2 - bromo-ethoxy) propane (EP 1072595) was prepared.

Preparation Example 19 - use of 1 - ethoxy-3 - iodopropane (EP 319479pg.21 Example 23) thereof.

Preparation Example 20 - with 2 - (2 - bromo-ethoxy) propane (FR 2638745pg.7 Example 4.1) was prepared.

Preparation Examples 24-37

The ammonium formate (5eq) was added portionwise to 10% palladium hydroxide Phi (II) carbon (10% w / w) and the Takes 4 - nitropyrazole (1eq) in ethanol (4-5mL.mmol^-1) Suspension, the reaction mixture was nitrogen Refluxed for 2 hours. The reaction mixture was filtered through Arbocel  washed with ethanol, in the real Air filtrate was concentrated. If it exists, so that the remaining ethanol was azeotroped with toluene to give the desired product Thereof.

25	R ⁵＝-CH ₃；R ⁶＝H ¹H NMR(DMSO-d ₆，400MHz)δ：2.04(s，3H)，4.45(br s，2H)，7.13(br s，2H).LRMS：m/z APCI+399，[MH] ⁺
25		26	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₃OCH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：1.82(m，2H)，2.04(s，3H)，3.17(s， 3H)，3.22(t，2H)，4.01(br s，2H)，4.27(t，2H)，7.45(br s，2H). LRMS：m/z APCI+235，[MNa] ⁺
27	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：1.03(t，3H)，2.02(s，3H)，3.35(q， 2H)，3.56(t，2H)，4.12(br s，2H)，4.35(t，2H)，5.37(br s，1H)，7.50(br s，1H).LRMS：m/z APCI+213，[MH] ⁺	26
27		28	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂OCH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：2.04(s，3H)，3.16(s，3H)，3.53(t， 2H)，4.07(br s，2H)，4.40(t，2H)，7.47(br s，2H).LRMS：m/z APCI+ 221，[MNa] ⁺
29	R ⁵＝-CH ₂CH ₃；R ⁶＝-(CH ₂) ₂OCH ₃ ¹H NMR(CDCl ₃，400MHz)δ：1.20(t，3H)，2.53(q，2H)，3.32(s，3H)， 3.80(t，2H)，4.46(t，2H).LRMS：m/z APCI+213，[MH] ⁺	28
29		30	R ⁵＝-CH ₂CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃ ¹H NMR(CDCl ₃，400MHz)δ：1.14(t，3H)，1.23(t，3H)，2.55(q，2H)， 3.50(q，2H)，3.84(t，2H)，4.43(t，2H).LRMS：m/z APCI+227[MH] ⁺
31	R ⁵＝-CH(CH ₃) ₂；R ⁶＝-(CH ₂) ₂OCH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：1.15(d，6H)，2.95(m，1H)，3.17(s， 3H)，3.55(t，2H)，4.07(br s，2H)，4.41(t，2H)，7.50(br s，2H). LRMS：m/z APCI+227，[MH] ⁺	30

32	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂O(CH ₂) ₂CH ₃ ¹H NMR(CDCl ₃，400MHz)δ：0.85(t，3H)，1.55(m，2H)，2.20(s，3H)， 3.42(t，2H)，3.85(t，2H)，4.43(t，2H).LRMS：m/z APCI+227，[MH] ⁺
32		33	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂OCH(CH ₃) ₂ ¹H NMR(CDCl ₃，400MHz)δ：1.08(d，6H)，2.23(s，3H)，3.58(m，1H)， 3.83(t，2H)，4.39(t，2H).LRMS APCI+m/z 227[MH] ⁺
34	R ⁵＝-(CH ₂) ₂CH ₃；R ⁶＝-(CH ₂) ₂OCH ₃ ¹H NMR(CDCl ₃，400MHz)δ：0.83(t，3H)，1.62(m，2H)，2.43(m，2H)， 3.36(s，3H)，3.78(m，2H)，4.46(m，2H).LRMS TSP+m/z 227[MH] ⁺	33
34		35	R ⁵＝-(CH ₂) ₂CH ₃；R ⁶＝-CH ₃ ¹H NMR(CDCl ₃，400MHz)δ：0.95(t，3H)，1.62(m，2H)，2.53(t，2H)， 2.80(br s，2H)，4.10(s，3H).LRMS TSP+m/z 205[MNa] ⁺
36	R ⁵＝-CH ₃；R ⁶＝-CH(CH ₃) ₂ ¹H NMR(CDCl ₃，400MHz)δ：1.42(d，6H)，2.23(s，3H)，5.55(m，1H). LRMS：m/z APCI+183，[MH] ⁺	35
36		37	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₃OCH ₂CH ₃ ¹H NMR(CDCl ₃，400MHz)δ：1.03(t，3H)，1.82(m，2H)，2.02(s，3H)， 3.24(t，2H)，3.48(q，2H)，4.05(m，2H)，4.28(t，2H)，7.48(br m，2H). LRMS APCI m/z 227[MH] ⁺

PREPARATION 38-51

The appropriate 4 - amino-pyrazole-5 - carboxamide (see Preparation Example 24-37) (1eq) and carbonyldiimidazole Imidazole (1eq) in N, N-dimethylformamide (3.8mL.mmol^-1) Was stirred at room temperature under a nitrogen For 1 hour. The reaction was then heated at 80 ℃ for 18 hours. Reaction was concentrated in vacuo Mixture, and the residue was triturated with acetone. The resulting solid was filtered and dried to give the desired product.

43	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：1.00(t，3H)，2.19(s，3H)，3.34(q， 2H)，3.67(t，2H)，4.44(t，2H)，11.02(br s，2H).LRMS：m/z APCI ^-237， [M-H] ^-
43		44	R ⁵＝H；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：0.97(s，3H)，3.36(q，2H)，3.70(t， 2H)，4.51(t，2H)，7.34(s，1H)，10.93(br s，1H)，11.07(br s，1H)
45	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₃OCH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：1.82(m，2H)，2.18(s，3H)，3.17(s， 3H)，3.26(t，2H)，4.32(t，2H)，11.00(br s，2H).LRMS：m/z(APCI-) 237，[M-H] ^-	44
45		46	R ⁵＝-CH(CH ₃) ₂；R ⁶＝-(CH ₂) ₂OCH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：1.19(d，6H)，3.10(m，1H)，3.17(s， 3H)，3.66(t，2H)，4.48(t，2H)，11.00(s，1H)，11.03(s，1H). LRMS：m/z APCI+253，[MH] ⁺
47	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂O(CH ₂) ₂CH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：0.74(t，3H)，1.39(m，2H)，2.20(s， 3H)，3.26(t，2H)，3.67(t，2H)，4.46(t，2H)，11.04(s，2H).LRMS：m/z APCI+253，[MH] ⁺	46
47		48	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂OCH(CH ₃) ₂ ¹H NMR(DMSO-d ₆，400MHz)δ：0.96(d，6H)，2.19(s，3H)，3.45(m， 1H)，3.65(t，2H)，4.40(t，2H)，11.00(br s，2H).LRMS APCI-m/z 251[M-H] ^-

49	R ⁵＝-CH ₃；R ⁶＝H ¹H NMR(DMSO-d ₆，400MHz，tautomers)δ：2.18(s，1.5H)，2.20(s， 1.5H)，10.70(br s，1H)，10.90(br s，0.5H)，10.92(br s，0.5H)，13.45 (br s，0.5H)，13.49(br s，0.5H).LRMS：m/z ES+189，[MNa] ⁺
49		50	R ⁵＝-(CH ₂) ₂CH ₃；R ⁶＝-(CH ₂) ₂OCH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：0.86(t，3H)，1.54(m，2H)，2.58(t， 2H)，3.16(s，3H)，3.65(t，2H)，4.48(t，2H)，11.06(s，2H).LRMS APCI+m/z 253[MH] ⁺
51	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₃OCH ₂CH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：1.08(t，3H)，1.90(m，2H)，2.19(s， 3H)，3.35(m，4H)，4.38(t，2H)，11.00(br s，2H).LRMS：m/z APCI ^- 237，[M-H] ^-	50

Preparation Example 52 to 65

Method A (Preparation Example 52,55,56,58 and 65): the N-ethyl diisopropylamine (2-2.5eq) Added to the appropriate dione (see Preparation Examples 38,41,42,44 and 50) (1eq) phosphoryl Chlorine (3mL.mmol^-1) Solution, and the resulting solution was heated under reflux for 18 hours. Cooling Mixing Matter, concentrated in vacuo, and the residue was dissolved in ethyl acetate (3.5mL.mmol^-1), Carefully with Water (3.5mL.mmol^-1) Washing. The organic solution was evaporated in vacuo, the crude product was subjected to column chromatography on silica gel Spectrum, eluting with ethyl acetate: pentane elution (20:80 to 60:40) to give the desired compound.

Method B (Preparation Example 53,54,57,59,60,61,62 and 63): tetraethyl Ammonium chloride (3eq) and phosphorous oxychloride (15eq) was added to the appropriate dione (see Preparation 39, 40, 43,45-48 and 51) (1eq) in acetonitrile (5-10mL.mmol^-1), And the resulting solution was back Was heated under reflux for 18 hours. The mixture was cooled, concentrated in vacuo, and the residue was dissolved in ethyl acetate Ester (3.5mL.mmol^-1), Carefully washed with water (3.5mL.mmol^-1) Washing. There was evaporated in vacuo Organic solution, the crude product was purified by column chromatography through silica gel, using ethyl acetate: pentane elution (20:80 To 60:40) to give the desired compound.

57	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃ ¹H NMR(CDCI ₃，400MHz)δ：1.08(t，3H)，2.60(s，3H)，3.42(q，2H)， 3.81(t，2H)，4.84(t，2H).LRMS APCI+m/z 275[MH] ⁺
57		58	R ⁵＝H；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃ ¹H NMR(CDCl ₃，400MHz)δ：1.04(t，3H)，3.42(q，2H)，3.86(t，2H)， 4.88(t，2H)，8.23(s，1H).LRMS：m/z APCI+261，[MH] ⁺
59	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₃OCH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：2.05(m，2H)，2.49(s，3H)，3.16(s， 3H)，3.32(t，2H)，4.65(t，2H).LRMS：m/z APCI+276，[MH] ⁺	58
59		60	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂OCH(CH ₃) ₂ ¹H NMR(400MHz，CDCl ₃)δ：0.91(d，6H)，2.50(s，3H)，3.40(m，1H)， 3.70(t，2H)，4.70(t，2H).LRMS APCI+m/z 289[MH] ⁺
61	R ⁵＝-CH(CH ₃) ₂；R ⁶＝-(CH ₂) ₂OCH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：1.38(d，6H)，3.18(s，3H)，3.39(m， 1H)，3.74(t，2H)，4.77(t，2H).LRMS：m/z APCI+289，[MH] ⁺	60
61		62	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₂O(CH ₂) ₂CH ₃ ¹H NMR(CDCl ₃，400MHz)δ：0.76(t，3H)，1.45(m，2H)，2.62(s，3H)， 3.31(t，2H)，3.82(t，2H)，4.82(t，2H).LRMS：m/z APCI+289，[MH] ⁺
63	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₃OCH ₂CH ₃ ¹H NMR(CDCl ₃，400MHz)：δ：0.97(t，3H)，2.06(m，2H)，2.51(s，3H)， 3.36(m，4H)，4.66(m，2H)	62
63		64	R ⁵＝-CH ₃；R ⁶＝H ¹H NMR(DMSO-d ₆，400MHz)δ：2.52(m，3H).LRMS ES-m/z 201 [M-H] ^-

65	R ⁵＝-(CH ₂) ₂CH ₃；R ⁶＝-(CH ₂) ₂OCH ₃ ¹H NMR(CDCl ₃，400MHz)δ：0.99(t，3H)，1.83(m，2H)，2.99(t，2H)， 3.28(s，3H)，3.80(t，2H)，4.83(t，2H).LRMS APCI+m/z 289[MH] ⁺

Preparation Example 66

N-(5 - chloro-1 - methyl-3 - propyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl) -4 - methyl- Pyridine-2 - ylamine

Dichloride in Preparation Example 52 (8g, 32.6mmol) and 2 - amino -4 - methyl-pyridine (10.6g, 97.9mmol) in dimethylsulfoxide (60mL) was stirred at 70 ℃ for 18 hours. The mixture was extracted with ethyl acetate (200mL), washed with water (3 × 100mL) and brine (70mL) wash Polyester. The organic solution was dried over magnesium sulfate, and concentrated in vacuo. The crude product was subjected to silica gel column chromatography Spectrum eluting with dichloromethane: acetonitrile 100:0 to 90:10, to give the title compound as Yellow solid, 5g.

¹H-NMR(CDCl ₃，400MHz)δ：1.00(t，3H)，1.83(m，2H)，2.43(s，3H)，2.91(t，2H)， 4.41(s，3H)，6.77(br s，1H)，7.89(br m，2H).LRMS：m/z ES+317[MH] ⁺

Preparation Example 67

N-(5 - chloro-1 - methyl-3 - propyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl) -5 - methyl- Pyridine-2 - ylamine

Dichloride of Preparation Example 52 and 2 - amino-5 - methyl-pyridine as starting materials, with 50:501 - methyl - 2 - pyrrolidone: dimethyl sulfoxide as a solvent, prepared in Example 66 by means of a square Preparation of the compound. The crude product was purified by column chromatography on silica gel using pentane: ethyl acetate 100:0 to 60:40 as eluent.

¹H NMR(DMSO-d ₆，400MHz)δ：0.90(t，3H)，1.72(m，2H)，2.25(s，3H)，2.75(t， 2H)，4.20(s，3H)，7.70(d，1H)，7.85(d，1H)，8.18(s，1H).LRMS：ES+m/z 339 [MNa] ⁺

Preparation Example 68

N-[5 - chloro-3 - ethyl-1 - (2 - methoxyethyl)-1H-pyrazolo [4,3-d] pyrimidin-7 - Yl] -4 - methyl-pyridin-2 - ylamine

Dichloride of Preparation Example 56 and 2 - amino - 4 - methyl-pyridine as starting materials, by means of the system Preparation Example 66 The compound was prepared. The crude product was purified by column chromatography on silica gel using dichloromethane : Methanol 98:2 as eluent.

¹H NMR(CDClX，400MHz)δ：1.38(t，3H)，2.32(s，3H)，2.98(q，2H)，3.52(s，3H)， 3.92(t，2H)，4.73(t，2H)，7.58(d，1H)，8.17(s，1H)，8.36(d，1H)，10.11(br s， 1H).LRMS ES ^-m/z 345[M-H] ^-

Preparation Example 69

5 - chloro-1 - methyl-3 - propyl-N-(4 - pyrimidinyl)-1H-pyrazolo [4,3-d] pyrimidin-7 - Amine

N-Butyllithium (6.53mL, 2.5M solution in hexane, 16.32mmol) added to 4 - amino- Pyrimidine (1.55g, 16.32mmol) in tetrahydrofuran (25mL) solution was stirred at room temperature for 10 Minutes. From the preparation of Example 52 was added dichloride (1g, 4.08mmol) in tetrahydrofuran Furans (25mL) was added. The reaction mixture was stirred for 2 hours. The mixture was then cooled in ice, Aqueous ammonium chloride was added, and the mixture was extracted with ethyl acetate. The combined organic solution, the acid Magnesium sulfate, purified by column chromatography through silica gel, using dichloromethane: methanol 99:1, to give standard Title compound 500mg.

¹H NMR(DMSO-d ₆，400MHz)δ：0.93(t，3H)，1.74(m，2H)，2.81(t，2H)，4.19(s， 3H)，7.99(d，1H)，8.63(d，1H)，8.86(s，1H).LRMS：m/z ESI ^-：302，[M-H] ^-

Preparation Example 70-77

The manner described in Preparation Example 69, from the appropriate dichloride material (Preparation 53, 54,57-60,62 and 64) prepared by the following general structural formula:

74	R ⁵＝-CH ₂CH ₃；R ⁶＝-(CH ₂) ₂OCH ₂CH ₃ ¹H NMR(CDCl ₃，400MHz)δ：1.25(t，3H)，1.41(t，3H)，3.02(q，2H)， 3.71(q，2H)，3.97(t，2H)，4.75(t，2H)，8.49(d，1H)，8.67(d，1H)，8.99 (s，1H).LRMS：m/z ES+348，[MH] ⁺
74		75	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₃OCH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：2.00(m，2H)，2.42(s，3H)，3.15(s， 3H)，3.20(m，2H)，4.55(t，2H)，7.95(d，1H)，8.62(d，1H)，8.88(s， 1H).LRMS：m/z(APCI+)320，[MH] ⁺
76	R ⁵＝-CH ₃；R ⁶＝-(CH ₂) ₃OCH ₂CH ₃ ¹H NMR(DMSO-d ₆，400MHz)δ：0.89(t，3H)，1.94(m，2H)，2.44(s， 3H)，3.17(t，2H)，3.28(q，2H)，4.56(t，2H)，7.87(d，1H)，8.62(d，1H)， 8.84(s，1H).LRMS APCI-m/z 346[M-H] ^-	75
76		77	R ⁵＝-CH ₃；R ⁶＝-CH(CH ₃) ₂ ¹H NMR(DMSO-d ₆，400MHz)δ：1.39(d，6H)，2.45(s，3H)，5.52(br s， 1H)，7.78(d，1H)，8.58(br s，1H)，8.81(s，1H).LRMS：m/z APCI+ 304，[MH] ⁺

Preparation Example 77: Using bis (trimethylsilyl) amide sodium instead of butyl lithium.

Preparation Example 78

N-[5 - chloro-3 - isopropyl-1 - (2 - methoxyethyl)-1H-pyrazolo [4,3-d] pyrimidine -7 - Yl] -4 - methyl-pyridin-2 - ylamine

Preparation Example 61 using the dichloride and 2 - amino - 4 - methyl-pyridine as starting materials, by means of the system Preparation Example 69 The compound was prepared. The crude product was purified by column chromatography on silica gel with methanol: Eluted with dichloromethane 0:100 to 5:95.

¹H NMR(DMSO-d ₆，400MHz)δ：1.36(d，6H)，2.36(s，3H)，3.25(s，3H)，3.34(m， 1H)，3.78(t，2H)，4.74，(m，2H)，7.65(m，1H)，8.21(m，1H)，8.38(m，1H)， LRMS：m/z APCI+361，[MH] ⁺

Preparation Example 79

N-[5 - chloro-3 - methyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-2 - Ylamine

Dichloride of Preparation Example 64 and 2 - amino - 4 - methyl-pyridine as starting materials, by means of the system Preparation Example 69 The compound was prepared. The crude product was triturated with ethyl acetate, filtered, the true Air concentrated to give the title product.

¹H NMR(DMSO-d ₆，400MHz)δ：2.35(s，3H)，2.43(s，3H)，7.00(d，1H)，7.84(s， 1H)，8.30(d，1H).LRMS：m/z ES+273，[M-H] ^-

Preparation Example 80

N-[5 - chloro-3 - methyl-1 - (2 - ethyl-propoxy)-1H-pyrazolo [4,3-d] pyrimidin-7 - Yl] -4 - methyl-pyridin-2 - ylamine

Dichloride of Preparation Example 62 and 2 - amino - 4 - methyl-pyridine as starting materials, by means of the system Preparation Example 69 The compound was prepared. The crude product was purified by column chromatography on silica gel with methanol: Eluted with dichloromethane 0:100 to 5:95.

¹H NMR(CDCl ₃，400MHz)δ：0.71(t，3H)，1.56(m，2H)，2.47(s，3H)，2.56(s， 3H)，3.51(t，2H)，3.91(t，2H)，4.79(t，2H)，6.91(br s，1H)，8.17(br s，1H)，8.42 (s，1H).LRMS：m/z APCI+361，[MH] ⁺

Preparation Example 81

N-[5 - chloro-3 - isopropyl-1 - (2 - methoxyethyl)-1H-pyrazolo [4,3-d] pyrimidine -7 - Yl] -5 - methyl-pyridin-2 - ylamine

Preparation Example 61 using the dichloride and 2 - amino-5 - methyl-pyridine as starting materials, by means of the system Preparation Example 69 The compound was prepared. The crude product was purified by column chromatography on silica gel with methanol: Eluted with dichloromethane 0:100 to 5:95.

¹H NMR(DMSO-d ₆，400MHz)δ：1.36(d，6H)，2.27(s，3H)，3.25(m，1H)，3.35(s， 3H)，3.77(t，2H)，4.72(br s，2H)，7.72(br d，1H)，8.05(br d，1H)，8.20(s，1H)

LRMS：m/z APCI+361，[MH] ⁺

Preparation Example 82

N-[5 - chloro-3 - methyl-1 - (2 - ethyl-propoxy)-1H-pyrazolo [4,3-d] pyrimidin-7 - Yl] -5 - methyl-pyridin-2 - ylamine

Dichloride of Preparation Example 62 and 2 - amino-5 - methyl-pyridine as starting materials, by means of the system Preparation Example 69 The compound was prepared. The crude product was purified by column chromatography on silica gel with methanol: Eluted with dichloromethane 0:100 to 5:95.

¹H NMR(CDCl ₃，400MHz)δ：0.74(t，3H)，1.60(m，2H)，2.32(s，3H)，2.55(s， 3H)，3.53(t，2H)，3.92(t，2H)，4.72(t，2H)，7.58(d，1H)，8.15(s，1H)，8.38(d，1H)

LRMS：m/z APCI+361，[MH] ⁺

Preparation Example 83

N-(5 - chloro-1 - methyl-3 - propyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl) pyrazine-2 - Ylamine

Dichloride of Preparation Example 52 and 2 - amino-1 ,4 - pyrazine as a starting material, prepared by means of Example 69 The compound was prepared.

¹H NMR(CD ₃OD，400MHz)δ：0.99(t，3H)，1.80(m，2H)，2.89(t，2H)，4.23(s， 3H)，8.33(d，1H)，8.42(d，1H)，9.48(s，1H).LRMS：m/z ES+326，[MNa] ⁺

Preparation Example 84

N-(5 - chloro-1 - methyl-3 - propyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl) pyrimidin-2 - Ylamine

Dichloride of Preparation Example 52 and 2 - amino-pyrimidine as a starting material, by means of Preparation Example 69 The method of preparing the compound.

¹H NMR(400MHz，CDCl ₃)δ：0.94(t，3H)，1.77(m，2H)，2.81(m，2H)，3.86(s， 3H)，7.16(m，1H)，8.59(m，2H).LRMS APCI+m/z 304[MH] ⁺

Preparation Example 85

N-[5 - chloro-1 - (2 - ethoxy-ethyl) -3 - methyl-1H-pyrazolo [4,3-d] pyrimidin-7 - Yl] -6 - methyl-4 - yl amine

Dichloride of Preparation Example 57 and 4 - amino-6 - methyl-pyrimidine as starting materials, by means of the system Preparation Example 69 The compound was prepared. The crude product was purified by column chromatography on silica gel using pentane: 66:34 ethyl acetate.

¹H NMR(DMSO-d ₆，400MHz)δ：1.40(t，3H)，2.44(s，3H)，2.47(s，3H)，3.51(q， 2H)，3.80(t，2H)，4.73(t，2H)，8.03(s，1H)，8.76(s，1H).LRMS：m/z APCI+348， [MH] ⁺

Preparation Example 86

N-(5 - chloro-1 - methyl-3 - propyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl) pyridazin-3 - Ylamine

Dichloride of Preparation Example 52 and 3 - amino-pyridazine as the starting material, preparation of Example 69 using The method of preparing the compound.

¹H NMR(DMSO-d ₆，400MHz)δ：0.90(t，3H)，1.72(m，2H)，2.79(m，2H)，4.27(s， 3H)，7.77(m，2H)，8.22(m，1H).LRMS APCI+m/z 304[MH] ⁺

Preparation Example 87

N-(5 - chloro-1 - methyl-3 - propyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl) -5 - methyl- [1,2,4] oxadiazol-3 - yl amine

Dichloride of Preparation Example 52 and 3 - amino-5 - methyl [1,2,4] oxadiazole (Heterocycles, EN; 57; 5; 2002; 811) as a starting material, by means of Preparation Example 69 The method of preparing the compound.

¹H NMR(DMSO-d ₆，400MHz)δ：0.94(t，3H)，1.77(m，2H)，2.14(s，3H)，2.83(m， 2H)，4.24(s，3H)，11.20(br s，1H).LRMS ES+m/z 330[MNa] ⁺

Preparation Example 88

N-(5 - chloro-1 - methyl-3 - propyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl)-1H-imidazole -2 - Yl amine

Dichloride of Preparation Example 52 and 2 - amino-1H-imidazole as a starting material, prepared by means of Example 69 The compound was prepared.

¹H NMR(CD ₃OD，400MHz)δ：1.01(t，3H)，1.72(m，2H)，2.81(m，2H)，4.33(s， 3H)，6.95(s，2H).LRMS ES-m/z 290[M-H] ^-

Preparation Example 89

5 - Chloro-N-(6 - methoxy-4 - pyrimidinyl)-1 - methyl-3 - propyl-1H-pyrazolo [4,3-d] Pyrimidin-7 - amine

Dichloride of Preparation Example 52 and 4 - amino-6 - methoxy-pyrimidine as starting materials, by means of Preparation Example 69 The compound was prepared. The crude product was purified by column chromatography on silica gel with acetic acid Ethyl: pentane 50:50 to 70:30.

¹H NMR(DMSO-d ₆，400MHz)δ：0.92(t，3H)，1.74(m，2H)，2.81(t，2H)，3.93(s， 3H)，4.21(s，3H)，7.40(s，1H)，8.57(s，1H).LRMS：m/z ES+356，[MNa] ⁺

Preparation Example 90

N-(5 - chloro-1 - isopropyl-3 - methyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl) -5 - methyl Yl-2 - ylamine

Dichloride of Preparation Example 53 and 2 - amino-5 - methyl-pyridine as starting materials, by means of the system Preparation Example 69 The compound was prepared.

¹H NMR(CDCl ₃，400MHz)δ：1.58(d，6H)，2.55(s，3H)，2.61(s，3H)，5.41(m， 1H)，7.61(m，1H)，8.14(m，1H)，8.41(m，1H)

Preparation Example 91

N-[5 - chloro-1 - (2 - ethoxy-ethyl) -3 - ethyl-1H-pyrazolo [4,3-d] pyrimidin-7 - Yl]-N-methyl-pyrimidin-4 - yl amine

Dichloride of Preparation Example 54 and N-methyl-pyrimidin-4 - amine as starting materials, by means of the system Preparation Example 69 The compound was prepared.

¹H NMR(CDCl ₃，400MHz)δ：1.25(t，3H)，1.41(t，3H)，3.02(q，2H)，3.71(q，2H)， 3.97(t，2H)，4.05(s，3H)，4.75(t，2H)，8.49(d，1H)，8.67(d，1H)，8.93(s，1H)

Preparation Example 92-98

Of N-ethyldiisopropylamine (3eq) and the appropriate HNR¹R ²Amine (3eq) was added to the appropriate two Chloride (see Preparation 56, 61 and 64) (1eq) in dimethylsulfoxide (2-3mL.mmol^-1) Solution was stirred overnight at 70 ℃. To the cooled reaction mixture was added piperazine-1 - Acid tert-butyl ester (5eq) and the further N-ethyl diisopropylamine (10eq), the reaction was 120 ℃ overnight. The cooling of the reaction mixture between ether and water (3:1 volume ratio) And the organic phase was dried over magnesium sulfate, concentrated in vacuo, to give the product.

Preparation Example 99

1 - (2 - ethoxy-ethyl)-4 - nitro-1H-pyrazole-3, 5 - dicarboxylic acid methyl ester

4 - nitro-1H-pyrazole-3, 5 - dicarboxylic acid methyl ester (2.0g, 8.83mmol) added And 2 - ethoxyethyl bromide (1.18mL, 10.45mmol) and potassium carbonate (1.32g, 9.56mmol) The N, N-dimethylformamide (35mL) solution, and the reaction mixture was stirred at room temperature for 48 Hours. The reaction mixture was concentrated in vacuo, partitioned between ethyl acetate (200mL) and water (100mL) of Room assignment. The organic layer was separated, dried over magnesium sulfate, and concentrated in vacuo. The crude product through silica Gel column chromatography eluting with pentane: ethyl acetate 100:0 to 70:30 to give the title product 1.63g.

¹H NMR(CDCl ₃，400MHz)δ：1.07(t，3H)，3.41(q，2H)，3.73(t，2H)，3.89(s，3H)， 3.94(s，3H)，4.76(t，2H).LRMS：m/z APCI+302，[MH] ⁺

Preparation of Example 100

1 - (2 - ethoxy-ethyl)-4 - nitro-1H-pyrazole-3 ,5 - two acid 3 - methyl ester

Diesters of Preparation 99 (1.63g, 5.4mmol) was added to potassium hydroxide (330mg, 5.9mmol) in methanol (20mL) solution, and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, and the crude product was dissolved in water, washed with ether. The aqueous phase was washed with 2M Hydrochloric acid, extracted into dichloromethane (3 × 100mL). The combined organic phases were combined, dried over magnesium sulfate Dry, concentrated in vacuo to give the title product 1.34g.

¹H NMR(CD ₃OD，400MHz)δ：1.07(t，3H)，3.47(q，2H)，3.80(t，2H)，3.88(s， 3H)，4.77(t，2H).LRMS：m/z APCI+288，[MH] ⁺

Preparation of Example 101

5 - carbamoyl -1 - (2 - ethoxy-ethyl)-4 - nitro-1H-pyrazole-3 - carboxylic acid methyl ester

Oxalyl chloride (1.2mL, 13.76mmol) and N, N-dimethylformamide (39μL) was added to Example 100 Preparation of carboxylic acid (1.33g, 4.63mmol) in dichloromethane (20mL) solution, and the reaction The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo from methylene chloride Azeotropically (3 × 50mL). The reaction mixture was dissolved in tetrahydrofuran (50mL), cooled in an ice bath However, with 0.880 ammonia solution (10mL) process. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, the remaining solution in methylene chloride (200mL) and water (50mL) Partitioned between. Organic phases were combined, dried over magnesium sulfate, and concentrated in vacuo to give the title product Matter 0.98g.

¹H NMR(DMSO-d ₆，400MHz)δ：1.03(t，3H)，3.38(q，2H)，3.70(t，2H)，3.86(s， 3H)，4.36(t，2H)，8.30(br s，1H)，8.46(br s，1H).LRMS APCI+m/z 287[MH] ⁺

Preparation Example 102

4 - amino-5 - carbamoyl -1 - (2 - ethoxyethyl)-1H-pyrazole-3 - carboxylic acid methyl ester

The Pd (OH)₂(100mg) was added to the nitro compound of Preparation 101 (970mg, 3.39mmol) in methanol (20mL) solution, and the reaction mixture was heated to reflux. Formic acid Bromide (1.07g, 16.97mmol), and the reaction mixture was stirred for 2 hours at reflux. In addition to filtering The catalyst, the reaction mixture was concentrated in vacuo to give the title product 870mg.

¹H NMR(DMSO-d ₆，400MHz)δ：1.04(t，3H)，3.32(q，2H)，3.66(t，2H)，3.78(s， 3H)，4.49(t，2H)，5.12(br s，2H)，7.50(br s，2H).LRMS APCI+m/z 257[MH] ⁺

Preparation Example 103

1 - (2 - ethoxy-ethyl) -5,7 - dioxo-4 ,5,6,7 - tetrahydro-1H-pyrazolo [4,3-d] Pyrimidine-3 - carboxylic acid methyl ester

The amine of Preparation 102 (570mg, 3.38mmol) in N, N-dimethylformamide (30mL) Was treated with carbonyldiimidazole (658mg, 4.06mmol) process, and the reaction mixture was stirred at room temperature Mixed for 1 hour, then the mixture was stirred at 90 ℃ for 18 hours. The reaction mixture was concentrated in vacuo, The crude product was suspended in acetone and sonicated for 30 minutes. The solid product was filtered in vacuo Dry.

¹H NMR(DMSO-d ₆，400MHz)δ：1.03(t，3H)，3.40(q，2H)，3.87(t，2H)，4.06(s， 3H)，4.98(t，2H).LRMS ES-m/z 281[M-H] ^-

Preparation Example 104

5,7 - dichloro-1 - (2 - ethoxyethyl)-1H-pyrazolo [4,3-d] pyrimidine-3 - carboxylic acid methyl Ester

Phosphorus oxychloride (934μL, 10.0mmol) and tetraethylammonium chloride (195mg, 1.50mmol) Preparation Example was added to 103-dione (140mg, 0.50mmol) in propionitrile (5mL) solution of the anti- Mixture is refluxed for 18 hours. The reaction mixture was concentrated in vacuo, the crude product was ethyl acetate Acetate (50mL) and water (50mL) partitioned between. The organic layer was dried over magnesium sulfate, concentrated in vacuo Shrink. The crude product was purified by column chromatography on silica gel using pentane: ethyl acetate 100:0 to 75:25 To afford the title product.

¹H NMR(CDClX，400MHz)δ：1.03(t，3H)，3.40(q，2H)，3.87(t，2H)，4.06(s，3H)， 4.98(t，2H).LRMS APCI+m/z 319[MH] ⁺

Preparation Example 105

5 - chloro-1 - (2 - ethoxyethyl) -7 - (4 - methyl-2 - ylamino)-1H-pyrazolo [4,3-d] pyrimidine-3 - carboxylic acid methyl ester

The dichloro compound of Preparation 104 (1.98g, 6.20mmol) was dissolved in dimethyl sulfoxide (10mL), the reaction mixture was treated with 2 - amino -4 - methyl-pyridine (1.34g, 12.4mmol) process. The reaction mixture was stirred at 75 ℃ for 5 hours. The reaction mixture in dichloromethane (300mL) And water (500mL) was partitioned between dichloromethane layer was separated. The organic layer was washed with water (3 × 100mL), dried over magnesium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, With dichloromethane: acetonitrile 100:0 to 98:2 as eluent. The crude product was extracted with ether (50mL) developed, over Filtered and concentrated in vacuo to give the title product 1.2g.

¹H NMR(CDCl3，400MHz)δ：1.06(t，3H)，2.49(s，3H)，3.62(q，2H)，4.00(t，2H)， 4.06(s，3H)，5.05(br，2H)，6.98(br s，1H)，8.16(br s，1H)，8.50(br s，1H)

LRMS APCI+m/z 391[MH] ⁺

Preparation Example 106

[5 - chloro-1 - (2 - ethoxyethyl) -7 - (4 - methyl-2 - ylamino)-1H-pyrazolo [4,3-d] pyrimidin-3 - yl] methanol

The chloro compound prepared in Example 105 (1.89g, 4.84mmol) was suspended in tetrahydrofuran (450mL) and the reaction mixture was cooled to -78 ℃. Added DIBAL (39mL, 1M toluene Solution, 39mmol), and the reaction mixture was warmed to -5 ℃. The reaction mixture was stirred at -5 ℃ under Stirred for 15 minutes, then re-cooled to -78 ℃, with aqueous ammonium chloride (10mL) quenched. The reaction mixture was warmed to room temperature in dichloromethane (200mL) and water (200mL) partitioned between. The mixture was filtered through Arbocel  organic layer was separated, dried over magnesium sulfate in vacuo Concentrated. The crude product was triturated with ethyl acetate, and the solid was filtered off to give the title product.

¹H NMR(CDCl ₃，400MHz)δ：1.1(t，3H)，2.46(s，3H)，3.61(m，2H)，3.94(m， 2H)，4.86(m，2H)，5.07(m，2H)，6.96(m，1H)，8.19(m，1H)，8.48(m，1H)

LRMS APCI+m/z 363[MH] ⁺

Preparation of Example 107

[5,7 - dichloro-1 - (2 - ethoxyethyl)-1H-pyrazolo [4,3-d] pyrimidin-3 - yl] methyl Alcohol

The DIBAL (62.5mL, 1M solution in tetrahydrofuran, 62.5mmol) dropwise to a cooled (-78 ℃) prepared from the ester of Example 104 (4g, 12.5mmol) in tetrahydrofuran (100mL) was dissolved Solution, once added to complete, then the reaction was stirred for 10 minutes. The mixture was then after 1 Heated up to -10 ℃, and then re-cooled to -78 ℃. Saturated ammonium chloride solution was carefully added Solution (45mL), and the mixture was warmed to room temperature, water (175mL) and methylene chloride (350mL) of Room assignment. The mixture was filtered through Arbocel , washed with dichloromethane (3 × 100mL), the combined organic solution was dried over sodium sulfate, and evaporated in vacuo. The crude product after Column chromatography on silica gel eluting with methanol: dichloromethane (1:99) as the eluent, to give the title Compound 2.56g. ...

¹H NMR(CDCl ₃，400MHz)δ：1.07(t，3H)，3.44(q，2H)，3.84(m，2H)，4.86(t，2H)， 5.09(s，2H).

3 - (tert-butyl-dimethyl-silyloxy methyl) -5,7 - dichloro-1 - (2 - ethoxy-ethyl Yl)-1H-pyrazolo [4,3-d] pyrimidine

Imidazole (637mg, 9.35mmol) and t-butyl dimethylsilyl chloride (1.41g, 9.35mmol) was added to the alcohol from the preparation of Example 107 (2.47g, 8.5mmol) in dichloromethane (50mL) solution, and the reaction was stirred at room temperature for 18 hours. The mixture was extracted with methylene chloride (250mL), washed with 10% aqueous potassium carbonate solution (175mL) was washed. The organic solution was acid Sodium sulfate, and evaporated in vacuo. The residue was subjected to silica gel column chromatography using methanol: dichloro Methane (1:99) as the eluent, to give the title compound 2.9g.

¹H NMR(CDCl ₃，400MHz)δ：0.00(s，6H)，0.78(s，9H)，0.93(t，3H)，3.29(q，2H)， 3.71(m，2H)，4.72(m，2H)，4.94(s，2H).LRMS：m/z APCI+405[MH ⁺]

Preparation of Example 109

N-[3 - (tert-butyl-dimethyl-silyloxy)-5 - chloro-1 - (2 - ethoxy-ethyl Yl)-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] pyrimidin-4 - yl amine

Bis (trimethylsilyl) amide sodium (1.12g, 6.12mmol) added to 4 - amino- Pyrimidine (580mg, 6.12mmol) in tetrahydrofuran (17mL) solution, and the solution was stirred at room temperature Mixed for 20 minutes. Add chloride from Preparation Example 108 (825mg, 2.04mmol) in tetrahydro- Furan (8mL) was added and the reaction was stirred at room temperature for 90 minutes. The reaction was washed with a saturated chlorine Aqueous ammonium hydroxide (50mL), washed with dichloromethane (100mL) was extracted. The organic extract was dried sulfur Sodium sulfate, and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using methanol: dichloro- Methane elution (three ninety-seven) to give the title compound 812mg.

¹H NMR(CDCl ₃，400MHz)δ：0.00(s，6H)，0.78(s，9H)，1.08(t，3H)，3.54(q，2H)， 3.82(m，2H)，4.63(m，2H)，4.91(s，2H)，8.29(d，1H)，8.53(d，1H)，8.76(s，1H).

Preparation Example 110

[5 - chloro-1 - (2 - ethoxyethyl) -7 - (pyrimidin-4 - ylamino)-1H-pyrazolo [4,3-d] Pyrimidin-3 - yl] methanol

The tetrabutylammonium fluoride (3.1mL, 1M solution in tetrahydrofuran, 3.1mmol) was added to from The compound prepared in Example 109 (715mg, 1.54mmol) in tetrahydrofuran (15mL) solution, and the Reaction was stirred at room temperature for 18 hours. The reaction was washed with water (40mL) was diluted mixture was extracted with ethyl Acetate (70mL) was extracted. The organic solution was dried over sodium sulfate, and evaporated in vacuo. Remnant Was subjected to silica gel column chromatography using methanol: dichloromethane (5:95) as the eluent, to obtain The title compound 450mg.

¹H NMR(CDCl ₃，400MHz)δ：1.22(t，3H)，3.69(m，2H)，3.98(m，2H)4.77(m， 2H)，5.08(s，2H)，8.58(m，1H)，8.64(m，1H)，8.97(m，1H).LRMS APCI+m/z 350[MH] ⁺

Preparation of Example 111

N-[3 - bromo-5 - chloro-1 - (2 - ethoxyethyl)-1H-pyrazolo [4,3-d] pyrimidine -7 - Yl] -4 - methyl-pyridin-2 - ylamine

The four methyl bromide (912mg, 2.75mmol) and triphenylphosphine (720mg, 2.75mmol) added Alcohol to Preparation Example 106 (830mg, 2.29mmol) in dichloromethane (35mL) solution, and the reaction The mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by column chromatography through silica gel, With dichloromethane: methanol 100:0 to 99:1 to afford the title product.

¹H NMR(CDCl ₃，400MHz)δ：0.92(m，3H)，2.63(s，3H)，3.58(m，2H)，3.91(m， 2H)，4.81(s，2H)，5.20(m，2H)，7.14(m，1H)，8.16(m，1H)，8.97(m，1H)

LRMS APCI+m/z 427[MH] ⁺

Preparation Example 112

N-[3 - bromo-5 - chloro-1 - (2 - ethoxyethyl)-1H-pyrazolo [4,3-d] pyrimidine -7 - Yl] - pyrimidin-4 - yl amine

Alcohol of Preparation Example 110 as a starting material, prepared in Example 111 using the compound prepared in Thereof.

¹H NMR(CDCl ₃，400MHz)δ：1.24(t，3H)，3.74(m，2H)，3.99(m，2H)4.84(m， 4H)，8.61(m，1H)，8.69(m，1H)，9.02(m，1H)

Preparation Example 113

(3S) -3 - (tert-butoxycarbonyl-amino) pyrrolidine-1 - carboxylic acid tert-butyl ester

The (3S) -3 - (tert-butoxycarbonyl-amino) pyrrolidine (1g, 5.37mmol) and triethylamine (1.38mL, 10.00mmol) was dissolved in dichloromethane (15mL), and the reaction mixture was stirred for 10 minutes Minutes. Then the reaction mixture was t-butyl dicarbonate (1.75g, 8.00mmol) treatment, the Stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo, the residue was subjected to silica gel column chromatography Spectrum, eluting with pentane: ethyl acetate 80:20 to give the title product as a white solid, 1.25g.

¹H NMR(CDCl ₃，400MHz)δ：1.39(s，18H)，1.81(m，1H)，2.15(m，1H)，3.13(m， 1H)，3.40(m，2H)，3.58(m，1H)，4.17(m，1H)，4.62(m，1H).LRMS ES+m/z 309 [MNa] ⁺

Preparation Example 114

(3R) -3 - (tert-butoxycarbonyl-amino) pyrrolidine-1 - carboxylic acid tert-butyl ester

Using (3R) -3 - (tert-butoxycarbonyl-amino) pyrrolidine with the method as in Production Example 113 Preparation of the compound.

¹H NMR(CDCl ₃，400MHz)δ：1.37(s，18H)，1.79(m，1H)，2.15(m，1H)，3.13(m， 1H)，3.40(m，2H)，3.58(m，1H)，4.16(m，1H)，4.62(m，1H).LRMS ES+m/z 309 [MNa] ⁺

Preparation Example 115

(3S) -1 - methyl-3 - (methylamino) pyrrolidine

At 0 ℃, lithium aluminum hydride solution (17mL, 1M solution in tetrahydrofuran, 17mmol) dropwise To a stirred solution of pyrrolidine Preparation Example 113 (600mg, 2.09mmol) in tetrahydrofuran (10mL) Solution. The reaction mixture was warmed to room temperature and then heated to reflux for 5 hours. The anti- Mixture is cooled with an ice bath to 0 ℃, then quenched solution was added sodium sulfate. The reaction mixture Extracted with ethyl acetate (100mL) was diluted ethyl acetate was decanted, washed with additional ethyl acetate Polyester residue. Organic phases were combined, dried over magnesium sulfate, and concentrated in vacuo to give the title product Matter 60mg.

¹H NMR(CD ₃OD，400MHz)δ：2.25-2.46(m，4H)，2.75(s，3H)，3.02(s，3H)，3.73- 4.08(m，3H)，LRMS APCI+m/z 115[MH] ⁺

Preparation Example 116

(3R) -1 - methyl-3 - (methylamino) pyrrolidine

Pyrrolidine of Preparation Example 114, using the method of Preparation Example 115 This compound was prepared.

¹H NMR(CD ₃OD，400MHz)δ：2.23-2.47(m，4H)，2.75(s，3H)，2.99(s，3H)，3.74- 4.06(m，3H).LRMS APCI+m/z 115[MH] ⁺

Preparation 117-123

The appropriate HNR¹R ²Amine (6.20mmol) was dissolved in tetrahydrofuran (30mL), under nitrogen the reaction Mixture is hexamethyldisilazane with sodium azide (sodium hexamethyldisilazide) (1.36g, 7.2mmol) process. The reaction mixture was stirred at room temperature for 20 minutes, then Preparation Example 54 and 55 from the appropriate dichloride compound or 57 (3.1mmol), stirred for 3 Hours. To the reaction mixture was added methanol (10mL) quenching, and concentrated in vacuo. The residue was Column chromatography on silica gel eluting with dichloromethane: methanol 100:0 to 95:5, to give the desired Product.

Preparation of Example 124

(2R) -2 - ethyl-piperazine dihydrochloride

The (2R) -2 - aminobutyric acid (1.57g, 15.22mmol) was dissolved in ethanol (40mL), and the solution With thionyl chloride (5mL, 63.8mmol) process. The reaction mixture was heated under reflux for 70 small Time. The reaction mixture was cooled and concentrated in vacuo. The residue was mixed with toluene (50mL) azeotrope, Give a clear oil. The oil (2.78g, 16.58mmol) was dissolved in dichloromethane (50mL), the solution Was treated with glycine benzyl ester (carbobenzyloxyglycine) (3.47g, 16.58mmol), 1 - hydroxybenzotriazole hydrate (2.55g, 16.65mmol), 1 - (3 - dimethylaminopropyl) -3 - Ethylcarbodiimide hydrochloride (3.18g, 16.59mmol) and triethylamine (6.9mL, 49.5mmol) Treatment. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was washed with water, lemon Acid, sodium bicarbonate solution and brine, then dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography through silica gel, using ethyl acetate: pentane 50:50 eluent. The crude product (4.22g, 13.08mmol) was dissolved in methanol (100mL), the solution was washed with 10% Pd / C (450mg) Processing in 60psi of hydrogen and stirred at room temperature for 18 hours. The reaction mixture was passed through Arbocel  Filtered and the filtrate was concentrated in vacuo. The residue (1.6g, 11.25mmol) was dissolved in 1,2 - Dimethoxyethane (25mL), the solution was washed with 1M solution of borane in tetrahydrofuran (45mL, 45mmol) Treatment. The reaction mixture was heated to reflux for 18 hours, then quenched with methanol, at room temperature For 30 minutes. The reaction mixture was concentrated in vacuo, and the residue was dissolved in methanol (50mL), With a saturated solution of hydrogen chloride in dioxane (15mL) was treated. The solution was refluxed for 2 hours and then After concentrated in vacuo, and the residue was dissolved in ether (50mL). Solution was concentrated in vacuo to give Title product as a yellow oil, which solidified on standing. ...

¹H NMR(DMSO-d ₆，400MHz)δ：0.84(t，3H)，1.30(m，1H)，1.70(m，1H)，3.00- 4.10(br m，7H).

3 - bromo-tetrahydropyran

The tetrahydro-pyran-3 - ol (J.Org.Chem., 1985,50,1582) (4.66mL, 49mmol) was dissolved in dichloromethane (137mL), the solution with four methyl bromide (19.48g, 58mmol) Treatment. The reaction mixture was cooled to 0 ℃, with triphenylphosphine (17.98g, 69mmol) in dichloromethane Chloride was treated dropwise. The reaction mixture was warmed to room temperature and stirred for 4 hours. In a vacuum The reaction mixture was concentrated, the residue was purified by column chromatography through silica gel, using dichloromethane: methanol 98:2 to give the title product as a yellow oil, 6.3g.

¹H NMR(CDCl ₃，400MHz)δ：2.02(m，2H)，2.18(m，2H)，3.54(t，2H)，3.96(m， 2H)，4.31(m，1H).

Preparation of Example 126

2 - (2,2,2 - trifluoro-ethoxy) ethanol

Combined trifluoroethanol (36mL, 494mmol), ethylene carbonate (66.0g, 741mmol), Triethylamine (70mL, 494mmol) and tetrabutylammonium bromide (3.20g, 9.90mmol), and the reaction Was heated to reflux for 24 hours. The reaction mixture was distilled at atmospheric pressure, at 132 ℃ The range of 142 ℃ to obtain the title product.

¹H NMR(CDCl ₃，400MHz)δ：3.69-3.77(m，4H)，3.88(m，2H).

Preparation of Example 127

5 - methyl - 4 - nitro - 2 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-2H-pyrazol-3 - acid Amine

5 - methyl - 4 - nitro-2H-pyrazole-3 - carboxamide (US 4282361, Example 7) (2.0g, 11.80mol), an alcohol of Preparation 126 (2.03g, 14.16mmol) and triphenylphosphine (4.29g, 16.52mmol) was dissolved in tetrahydrofuran (30mL), the mixture was cooled in an ice bath. Dropping azobis Diisopropyl acid (3.20mL, 16.52mmol) in tetrahydrofuran (5mL) was added and the reaction mixture Compound at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, and the residue triturated with diethyl Chloride: ether 80:20 developed to give a white solid 884mg. Mother liquor was concentrated in vacuo, the The residue was triturated with methylene chloride, the solid was filtered to give another batch of white solid 584mg. However After purified by column chromatography on silica gel dichloromethane solution, with dichloromethane: ether 70:30 as eluent to give Of the product to another 1.49g. ...

¹H NMR(CD ₃OD，400MHz)δ：2.46(s，3H)，3.91(q，2H)，4.02(t，2H)，4.35(t，2H)

4 - amino - 5 - methyl - 2 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-2H-pyrazol-3 - acid Amine

Preparation of Example 127 from the pyrazole (1.46g, 4.93mmol) and palladium hydroxide (150mg) In methanol (50mL) was heated to reflux, was added portionwise ammonium formate (1.55g, 24.6mmol). Once inserted completely, the reaction was continued under reflux for 1 hour. Cooling Mixture was filtered through Arbocel , the filtrate was evaporated in vacuo to give the title compound, As an orange solid, 1.30g.

¹H NMR(CD ₃OD，400MHz)δ：2.16(s，3H)，3.84(q，2H)，3.91(t，2H)，4.53(t，2H)

LRMS：m/z ES+m/z 289[MNa] ⁺

Preparation of Example 129

3 - methyl-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl] -1,4 - dihydro-pyrazolo [4,3-d] Pyrimidine-5, 7 - dione

1,1 '- carbonyldiimidazole (1.2g, 7.4mmol) in acetonitrile (15mL) was heated to back Stream, after 25 minutes from the preparation of Example 128 was added dropwise pyrazole (1.3g, 4.93mmol) in acetonitrile (15mL) was added. The reaction was heated under reflux for another 1.5 hours and then added to the other 1,1 '- carbonyldiimidazole (400mg, 2.5mmol), the reaction was heated under reflux for another 18 Hours. The mixture was cooled, evaporated in vacuo, and the residue was triturated with ether, the resulting solid was filtered off Body, and dried to give the title compound as a white solid, 864mg.

¹H NMR(DMSO-d ₆，400MHz)δ：2.20(s，3H)，3.92(t，2H)，4.00(q，2H)，4.51(t， 2H)，11.08(s，2H).

Preparation of Example 130

5,7 - dichloro-3 - methyl-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidine

Prepared from the compound of Example 129 (2.1g, 7.18mmol), phosphorus oxychloride (10.02mL) And tetraethylammonium chloride (3.57g, 21.6mmol) in propionitrile (30mL) was heated to 100 ℃, for 18 hours. The mixture was cooled, evaporated in vacuo, the residue was mixed with toluene Azeotrope. The residue was partitioned between ethyl acetate and water, the layers were separated. The organic phase was sulfur Magnesium sulfate, concentrated in vacuo, the crude product was purified by column chromatography on silica gel, eluting with dichloromethane: Ethyl acetate (50:50) to give the title compound as a gum, 776mg.

¹H NMR(CDCl ₃，400MHz)δ：2.62(s，3H)，3.72(q，2H)，4.03(t，2H)，4.89(t，2H)

Preparation of Example 131

5 - amino-1 - methyl-1H-pyridin-2 - one

Trifluoroacetic acid (10mL) was added dropwise to a cold (1 - methyl-6 - oxo-1 ,6 - dihydropyridine -3 - Yl)-carbamic acid tert-butyl ester (Heterocycles 1995; 40; 2; 831-836) (2.87g, 12.8mmol) in dichloromethane (80mL) solution, and the reaction at room temperature For 18 hours. The mixture was concentrated in vacuo, the residue was purified by column chromatography through silica gel, to With dichloromethane: methanol: 0.88 ammonia (90:10:1) as eluent to give the title compound, The red / brown solid, 1.90g.

¹H NMR(CD ₃OD，400MHz)δ：3.50(s，3H)，6.47(d，1H)，7.04(d，1H)，7.26(dd， 1H).

Preparation of Example 132

5 - amino-2 ,3 - dimethyl-pyridine dihydrochloride

The cold 0.88 ammonia (344mL, 6.2mol) was added to 5 - bromo-2 ,3 - dimethylpyridine (Zeitschrift fur Chemie 28; 2; 1988; 59-60) (35.1g, 188.6mmol) And copper oxide (330mg, 2.3mmol), the mixture was stirred vigorously and then transferred to a sealed Container, at 100 ℃ for 18 hours. The mixture was cooled to 10 ℃, washed with 2M sulfuric acid and To pH 10, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, Dried over sodium sulfate, and concentrated in vacuo. The product was dissolved in ether, the solution was cooled to 0 ℃, 1M hydrochloric acid was added dropwise. The resulting mixture was stirred for 30 minutes, the precipitate was filtered, washed with ether, the Dried in vacuo to give the title compound 32.9g.

¹H NMR(DMSO-d ₆，400MHz)δ：2.23(s，3H)，2.50(s，3H)，7.10-7.80(m，5H).

LRMS：m/z ES+123.6[MH] ⁺

Preparation of Example 133

4 - amino-6 - methyl-pyrimidine

In sealed containers, the mixture of 4 - chloro-6 - methyl-pyrimidine (Recl.Trav.Chim. Pays-Bas.84; 1965,1101-1106) (1g, 7.81mmol) and 0.88 ammonia (25mL) The mixture was heated at 100 ℃ for 18 hours. The mixture was cooled, concentrated in vacuo, and the residue Was purified by column chromatography through silica gel, using dichloromethane: methanol: 0.88 ammonia (95:5:0.5) as the Eluent, to give the title compound 560mg.

¹H NMR(CD ₃OD，400MHz)δ：2.30(s，3H)，6.40(s，1H)，8.23(s，1H).

Preparation of Example 134

[5 - chloro-1 - (2 - ethoxy-ethyl) -3 - methyl-1H-pyrazolo [4,3-d] pyrimidin-7 - Yl] -6 - methyl-pyridin-2 - ylamine

Bis (trimethylsilyl) amide sodium (1.99g, 10.85mmol) was added portionwise to the cold But 2 - amino-6 - methyl-pyridine (1.17g, 10.85mmol) in tetrahydrofuran (10mL) was In order to maintain the temperature below 25 ℃. Once inserted completely, then the solution was stirred for an additional 20 minutes Minutes and then added dropwise from the chloro compound prepared in Example 57 (1g, 3.63mmol) in tetrahydrofuran (15mL) solution in order to maintain the temperature below 25 ℃. The reaction was then stirred for another 2 hours. In ethyl acetate (100mL) with a 10% citric acid solution (100mL) partitioned between. The organic layer was separated, Dried over magnesium sulfate, and evaporated in vacuo. The residue was triturated with ether, the solid was filtered and dried, To give the title compound 595mg.

¹H NMR(CD ₃OD，400MHz)δ：0.93(t，3H)，2.45(s，3H)，2.49(s，3H)，3.61(q， 2H)，3.92(t，2H)，4.88(t，2H)，6.98(d，1H)，7.71(dd，1H)，8.21(br s，1H).

LRMS：m/z ES+m/z 369[MNa] ⁺

Preparation 135-141

Prepared according to the procedure similar to that described in Example 134 The following compounds were prepared.

A-compound purified by column chromatography through silica gel, using methanol: dichloromethane as the eluent, Then recrystallized from ethyl acetate.

B-compound purified by column chromatography using ethyl acetate: pentane (50:50 to 100:0) As eluent.

C-compound purified by column chromatography using ethyl acetate: methylene chloride as eluent.

Preparation Example 135:2 - amino - 4 - (trifluoromethyl) pyridine are as J.Med.Chem.41 (1); 1998; 96-101 prepared as described.

Preparation Example 136:4 - amino-2 - methyl-pyrimidine is as J.Het.Chem.14; 1413; Prepared as described in 1977.

Preparation Example 137: Preparation of the amine from Example 133.

Preparation of Example 142

5 - [5 - chloro-1 - (2 - ethoxy-ethyl) -3 - methyl-1H-pyrazolo [4,3-d] pyrimidin-7 - Amino] -1 - methyl-1H-pyridin-2 - one

From the chloro compound prepared in Example 57 (100mg, 0.36mol) and from Preparation Example 131 amine (230mg, 1.85mmol) in dimethyl sulfoxide (3mL) was stirred at room temperature For 4 hours. The mixture was partitioned between ethyl acetate (100mL) and water (200mL) was partitioned between points From each phase. The aqueous layer was extracted with ethyl acetate (2x), the combined organic solution was dried over magnesium sulfate, Evaporated in vacuo. The residue was triturated with ether, the solid was filtered and dried to give the title compound Matter, as a gray solid, 80mg.

¹H NMR(CD ₃OD，400MHz)δ：1.08(t，3H)，2.46(s，3H)，3.54(q，2H)，3.63(s， 3H)，3.87(t，2H)，4.76(t，2H)，6.63(d，1H)，7.69(dd，1H)，8.24(d，1H)

LRMS：m/z APCI+363[MH] ⁺

Preparation of Example 143

[5 - chloro-1 - (2 - ethoxy-ethyl) -3 - methyl-1H-pyrazolo [4,3-d] pyrimidin-7 - Yl] -5,6 - dimethyl-pyridin-3 - yl amine

From the chloro compound prepared in Example 57 (230mg, 0.84mmol), N-ethyl di-iso- Propylamine (437μL, 2.52mmol) and the amine from Preparative Example 132 (398mg, 2.52mmol) in Dimethyl sulfoxide (3mL) was stirred at room temperature for 2 hours. The mixture was diluted with water Buddhism and extracted with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate, evaporated in vacuo Fat, and the residue purified by column chromatography through silica gel, using dichloromethane: methanol (100:0 to 98:2) As eluent to give the title compound 160mg.

¹H NMR(CD ₃OD，400MHz)δ：1.09(t，3H)，2.36(s，3H)，2.47(s，3H)，2.48(s， 3H)，3.59(q，2H)，3.91(t，2H)，4.79(t，2H)，8.01(d，1H)，8.67(d，1H)

LRMS：m/z APCI+361[MH] ⁺

Preparation of Example 144

[5 - chloro-1 - (2 - ethoxy-ethyl) -1 - methyl-1H-pyrazolo [4,3-d] pyrimidin-7 - Yl] -6 - methoxy-pyridin-3 - yl amine

A mixture of 5 - amino-2 - methoxypyridine (1.13g, 9.1mmol) in dichloromethane (2mL) was Was added dropwise from the chloro compound prepared in Example 57 (500mg, 1.82mmol) in dichloromethane (8mL) solution, and the reaction was stirred at room temperature for 18 hours. The mixture was extracted with dichloro- Methane, washed with 10% citric acid solution (3 × 10mL), dried over magnesium sulfate, the reduction Pressure and evaporated to give the title compound as a pale pink solid.

¹H NMR(DMSO-d ₆，400MHz)δ：0.95(t，3H)，2.38(s，3H)，3.40(q，2H)，3.72(t， 2H)，3.86(s，3H)，4.80(t，2H)，6.91(m，1H)，7.92(m，1H)，8.38(m，1H)，9.13(s， 1H).LRMS：m/z APCI+363[MH] ⁺

Preparation of Example 145

4 - nitro-1 - (2 - ethyl-propoxy)-1H-pyrazole-3, 5 - dicarboxylic acid methyl ester

The isopropyl azodicarboxylate (14.2mL, 70mmol) was added to ice-cold 4 - nitro -1H-pyrazole-3, 5 - dicarboxylic acid methyl ester (EP 1241170, Preparation Example 10) (15g, 60mmol), 2 - propoxy ethanol (8.2mL, 70mmol) and triphenylphosphine (18.9g, 70mmol) In tetrahydrofuran (150mL) solution, and the reaction was stirred at 0 ℃ for 2.5 hours and then Room temperature and stirred for an additional 18 hours. The reaction was concentrated in vacuo, and the residue was subjected to silica gel column chromatography Spectrum, eluting with ethyl acetate: pentane as eluant, then the column using dichloromethane Alkyl as the eluent, to give the title compound as a solid, 14g.

¹H NMR(CD ₃OD，400MHz)δ：0.82(t，3H)，1.47(m，2H)，3.34(t，2H)，3.78(t， 2H)，3.91(s，6H)，4.76(t，2H).LRMS：m/z APCI+316[MH] ⁺

Preparation of Example 146

3 - (methoxycarbonyl)-4 - nitro-1 - (2 - ethyl-propoxy)-1H-pyrazol-5 - carboxylic acid

Prepared from the diester of Example 145 (14g, 44mmol) and potassium hydroxide (2.74g, 48mmol) in methanol (200mL) was stirred at room temperature for 18 hours. Concentrated in vacuo Condensation reaction mixture, the residue was suspended in water. The aqueous solution was washed with ether (3x), and Acidified with hydrochloric acid to pH 2-3, the solution was extracted with dichloromethane (9x). These combined organic extracts Extracting solution, dried over magnesium sulfate, and evaporated in vacuo to give the title compound as a white solid, 13.2g.

¹H NMR(CD ₃OD，400MHz)δ：0.83(t，3H)，1.49(m，2H)，3.36(t，2H)，3.80(t， 2H)，3.90(s，3H)，4.78(t，2H).LRMS：m/z APCI+302[MH] ⁺

Preparation of Example 147

5 - carbamoyl - 4 - nitro -1 - (2 - ethyl-propoxy)-1H-pyrazole-3 - carboxylic acid methyl ester

Oxalyl chloride (11.48mL, 132mmol) was added dropwise after 30 minutes cooling (-5 ℃) to come Preparation of the acid from Example 146 (13.2g, 44mmol) and N, N-dimethylformamide (150μL) Two Methylene chloride (140mL) solution, and the solution was stirred for 1 hour and then slowly warmed to room temperature, stirred Mixed with another 1.5 hours. The solution was evaporated in vacuo, and the residue was azeotroped with methylene chloride. Will Product was dissolved in tetrahydrofuran (150mL), the solution was cooled in an ice bath, was added dropwise after 10 minutes 0.88 ammonia (60mL). After one hour the reaction was warmed to room temperature and then evaporated in vacuo. The residue was triturated with water, the resulting solid was filtered off, and dried at 70 ℃, to give the title compound 10.22g.

¹H NMR(DMSO-d ₆，400MHz)δ：0.81(t，3H)，1.45(m，2H)，3.32(t，2H)，3.74(t， 2H)，3.96(s，3H)，4.40(t，2H)，8.33(br s，1H)，8.48(br s，1H).LRMS：m/z APCI+ 301[MH] ⁺

Preparation of Example 148

4 - amino-5 - carbamoyl -1 - (2 - ethyl-propoxy)-1H-pyrazole-3 - carboxylic acid methyl ester

The nitro compound prepared in Example 147 (10g, 33mmol) and palladium hydroxide on carbon Phi (933mg) In ethanol (180mL) was heated to 75 ℃, and ammonium formate (2.1g, 33.3mmol), The reaction was stirred for an additional 3 hours. The mixture was filtered through Arbocel , washed with ethanol sufficiently Washing combined filtrates evaporated in vacuo to give the title compound as a pale pink solid, 9.1g.

¹H NMR(CD ₃OD，400MHz)δ：0.84(t，3H)，1.51(m，2H)，3.40(t，2H)，3.83(t， 2H)，3.89(s，3H)，4.56(t，2H).LRMS：m/z APCI+271[MH] ⁺

Preparation of Example 149

5,7 - dioxo-1 - (2 - ethyl-propoxy) -4,5,6,7 - tetrahydro-1H-pyrazolo [4,3-d] Pyrimidine-3 - carboxylic acid methyl ester

Prepared from the compound of Example 148 (9g, 33mmol), 1,1 '- carbonyldiimidazole (5.4g, 33mmol) and N, N-dimethylformamide (400mL) was stirred at room temperature for 30 minutes. Then heated to 75 ℃ for 18 hours. Tlc analysis showed a surplus of raw materials, thus adding another Outside of 1,1 '- carbonyldiimidazole (400mg, 2.5mmol), and the mixture was stirred for additional 1.5 hours Time. The mixture was concentrated in vacuo, and the residue was suspended in water, stirred for 30 minutes. Filtered The resulting precipitate was dried to give the title compound as a pale pink solid, 6.05g.

¹H NMR(DMSO-d ₆，400MHz)δ：0.72(t，3H)，1.37(m，2H)，3.28(m，2H)，3.76(t， 2H)，3.82(s，3H)，4.64(t，2H)，10.77(s，1H)，11.37(s，1H).

Preparation of Example 150

5,7 - dichloro-1 - (2 - ethyl-propoxy)-1H-pyrazolo [4,3-d] pyrimidine-3 - carboxylic acid methyl Ester

Prepared from the compound of Example 149 (3g, 10mmol), phosphorus oxychloride (14.2mL, 152mmol) and tetraethylammonium chloride (3.95g, 30mmol) in propionitrile (80mL) in a mixture of Heated at 115 ℃ for 18 hours. The mixture was evaporated in vacuo, and the residue was resuspended in Phosphorus oxychloride (15mL, 160mmol) and propionitrile (80mL), and the reaction was stirred at 115 ℃ another Outside 18 hours. The mixture was concentrated in vacuo, and the residue azeotroped with toluene. Carefully make residual Residue partitioned between ethyl acetate and water and the layers were separated, the aqueous phase extracted with additional ethyl acetate Take. The combined organic solution was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. Coarse Product was purified by column chromatography through silica gel, using pentane: ethyl acetate (75:25) as the eluent, To give the title compound 3.1g. ...

¹H NMR(DMSO-d ₆，400MHz)δ：0.65(t，3H)，1.33(m，2H)，3.26(t，2H)，3.82(t， 2H)，3.93(s，3H)，4.94(t，2H).

5 - chloro-7 - (4 - methyl-pyridin-2 - yl-amino) -1 - (2 - ethyl-propoxy)-1H-pyrazolo [4,3-d] pyrimidine-3 - carboxylic acid methyl ester

Preparation Example 150, from the chloro compound (1g, 3mmol) and 2 - amino -4 - methyl-pyridine Fixed (389mg, 3.6mmol) in dimethyl sulfoxide (4.1mL) was stirred at room temperature for 4 Hours. The mixture was partitioned between ethyl acetate and water, the layers were separated. The aqueous phase with ethyl acetate Acetate extraction (3x), the combined organic solution was washed with water (3x) and brine, dried over magnesium sulfate and then dried Dry, evaporate in vacuo. The crude product was purified by column chromatography on silica gel, using ethyl acetate: pentane ladder Elution (20:80 to 50:50) to give the title compound 452mg.

¹H NMR(CDCl ₃，400MHz)δ：0.72(m，3H)，1.25(m，2H)，2.47(s，3H)，3.52(t， 2H)，3.99(m，2H)，4.07(s，3H)，4.98(m，2H)，6.90(s，1H)，7.23(s，1H)，8.18(s， 1H).

Preparation of Example 152

N-[5 - chloro-3 - hydroxy-1 - (2 - ethyl-propoxy)-1H-pyrazolo [4,3-d] pyrimidine -7 - Yl] -4 - methyl-pyridin-2 - ylamine

The diisobutyl aluminum hydride (4.95mL, 1M solution in tetrahydrofuran, 4.95mmol) after 10 Minutes added to the cooled (-78 ℃) from the compound of Preparation 151 (250mg, 0.62mmol) In tetrahydrofuran (6.5mL) solution, once joined completely, then the reaction was warmed to -10 ℃, Stirred for 10 minutes. The solution was re-cooled to -78 ℃, adding additional diisobutyl aluminum hydride (2mL, 1M solution in tetrahydrofuran, 2mmol), and the mixture was warmed to -5 ℃, stirred for 30 minutes Minutes. The reaction was recooled to -78 ℃, with ammonium chloride solution (5mL) quenched. The mixture In water (50mL) and methylene chloride (50mL) was partitioned between filtered through Arbocel , with methylene Washed methane. Filtrate was separated, and the organic phase was dried over magnesium sulfate, and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using methanol: dichloromethane (1:99) to give the title Compound as a yellow solid, 112mg. ...

¹H NMR(CD ₃OD，400MHz)δ：0.70(t，3H)，1.50(m，2H)，2.43(s，3H)，3.50(m， 2H)，3.95(t，2H)，4.82(m，4H)，7.00(s，1H)，8.19(s，1H)，8.38(s，1H).

LRMS：m/z APCI+377[MH] ⁺

N-[3 - (tert-butyl-dimethyl-silyloxy)-5 - chloro-1 - (2 - ethoxy-ethyl Yl)-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -6 - methyl-pyridin-2 - ylamine

Bis (trimethylsilyl) amide sodium (677.1mg, 3.7mmol) was added portionwise to the cold But 2 - amino-6 - methyl-pyridine (400mg, 3.7mmol) in tetrahydrofuran (5mL) solution, To maintain the temperature at 25 ℃, once joined completely, then the solution was stirred for 20 minutes. Dropping to Since the chloro compound prepared in Example 108 (500mg, 1.23mmol) in solution, and then the reaction Stirred at room temperature for 1 hour. Ammonium chloride solution was added to quench the reaction, and the mixture in methylene chloride Alkyl between the water allocations. The layers were separated, and the organic phase washed with water and brine, then dried acid Magnesium sulfate, and evaporated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with dichloromethane: Methanol (100:0 to 90:10) to give the title compound as a yellow solid, 450mg. ...

¹H NMR(CD ₃OD，400MHz)δ：0.12(s，6H)，0.90(s，9H)，1.13(t，3H)，2.49(s， 3H)，3.61(q，2H)，3.93(t，2H)，4.84(t，2H)，4.98(s，2H)，6.98(m，1H)，7.73(t， 1H)，8.25(m，1H).LRMS：m/z APCI+477[MH] ⁺

[5 - chloro-1 - (2 - ethoxyethyl) -7 - (6 - methyl-2 - ylamino)-1H-pyrazolo [4,3-d] pyrimidin-3 - yl] methanol

Preparation Example 153 from the protected alcohol (450mg, 0.94mmol) and tetrabutylammonium fluoride Ammonium (1.89mL, 1M solution in tetrahydrofuran, 1.89mmol) in tetrahydrofuran (5mL) in a mixture of Was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo, and the residue in dichloromethane And partitioned between water. The phases were separated, and the organic layer washed with water and brine, then dried over magnesium Dried and evaporated in vacuo. The product was triturated with ether to give the title compound as a pale yellow Solid, 260mg.

¹H NMR(DMSO-d ₆，400MHz)δ：0.92(t，3H)，2.43(s，3H)，3.56(q，2H)，3.83(t， 2H)，4.67(d，2H)，4.77(t，2H)，7.01(d，1H)，7.78(m，1H)，8.03(d，1H)，10.08(s， 1H).LRMS：m/z APCI+363[MH] ⁺

Preparation of Example 155

N-[5 - chloro-3 - (chloromethyl) -1 - (2 - ethoxyethyl)-1H-pyrazolo [4,3-d] pyrimidine -7 - Yl] -4 - methyl-pyridin-2 - ylamine

Prepared from the alcohol of Example 106 (1.80g, 5.00mmol) was dissolved in dichloromethane (15mL), The solution was treated with thionyl chloride (1.50mL, 17mmol) process. The reaction mixture was stirred at room temperature Mixed for 18 hours and concentrated in vacuo. The residue was azeotroped with toluene, and dried in vacuo. The crude product was purified by column chromatography on silica gel with dichloromethane: methanol (100:0 to 95:5), To obtain the title product 980mg.

¹H NMR(CDCl ₃，400MHz)δ：0.92(t，3H)，2.63(s，3H)，3.58(m，2H)，3.91(m， 2H)，4.81(s，2H)，5.20(m，2H)，7.14(m，1H)，8.16(m，1H)，8.97(m，1H)

LRMS：m/z APCI+381[MH] ⁺

Preparation of Example 156

N-[5 - chloro-3 - (chloromethyl) -1 - (2 - ethyl-propoxy)-1H-pyrazolo [4,3-d] pyrimidine -7 - Yl] -4 - methyl-pyridin-2 - ylamine

Thionyl chloride (170μL, 23.4mmol) was added to the hydroxyl group from the compound of Preparation 152 Material (220mg, 0.58mmol) in dichloromethane (2mL) solution, and the solution stirred at room temperature 2.5 hours. The reaction mixture was evaporated in vacuo to give the title compound as a pale yellow foam.

¹H NMR(CDCl ₃，400MHz)δ：0.60(t，3H)，1.30(m，2H)，2.69(s，3H)，3.41(t，2H)， 3.91(m，2H)，4.96(s，2H)，5.24(m，2H)，7.23(m，1H)，8.16(d，1H)，9.06(s，1H).

LRMS：m/z ES+395[MH] ⁺

Preparation of Example 157

N-[5 - chloro-3 - (chloromethyl) -1 - (2 - ethoxyethyl)-1H-pyrazolo [4,3-d] pyrimidine -7 - Yl] - pyrimidin-4 - yl amine

Prepared according to the procedure similar to that described in Example 156, Example 110 was prepared from the alcohol from the obtained The title compound as a yellow solid.

¹H NMR(CDCl ₃，400MHz)δ：1.20(t，3H)，3.68(q，2H)，3.96(t，2H)，4.75(t，2H)， 4.88(s，2H)，8.62(d，1H)，8.69(d，1H)，9.00(s，1H).LRMS：m/z APCI+368 [MH] ⁺

Preparation of Example 158

N-[5 - chloro-3 - (chloromethyl) -1 - (2 - ethoxyethyl)-1H-pyrazolo [4,3-d] pyrimidine -7 - Yl] -6 - methyl-pyridin-2 - ylamine

Prepared according to the procedure similar to that described in Example 156, Example 154 was prepared from the alcohol from the obtained The title compound as a white foam.

¹H NMR(CD ₃OD，400MHz)δ：0.87(t，3H)，2.90(s，3H)，3.47(q，2H)，3.89(t， 2H)，4.96(s，2H)，5.30(t，2H)，7.19(d，1H)，8.19(t，1H)，9.04(d，1H).LRMS：m/z APCI+381[MH] ⁺

Preparation of Example 159

N-[5 - chloro-1 - (2 - ethoxy-ethyl) -3 - methoxy-methyl-1H-pyrazolo [4,3-d] pyrimidine Pyridine -7 - yl] -4 - methyl-pyridin-2 - ylamine

Sodium methoxide (25% methanol solution, 8.4mL, 39.5mmol) was added to Preparation Example 155 from The chloro compound (3g, 7.9mmol) in methanol (30mL) solution, and the reaction was incubated at room temperature Stirred for 72 hours. The mixture was evaporated in vacuo, the residue was divided between dichloromethane and water, With. The layers were separated and the organic phase washed with water and evaporated in vacuo. Product was subjected to silica gel column chromatography Spectrum, eluting with ethyl acetate as eluent to give the title compound as a yellow solid.

¹H NMR(CD ₃OD，400MHz)δ：1.10(t，3H)，2.44(s，3H)，3.35(m，2H)，3.45(s， 3H)，3.60(q，2H)，3.93(t，2H)，4.72(s，2H)，6.99(s，1H)，8.19(s，1H)，8.33(s， 1H).

Preparation of Example 160

N-[5 - chloro-3 - methoxy-1 - (2 - ethyl-propoxy)-1H-pyrazolo [4,3-d] pyrimidine Pyridine -7 - yl] -4 - methyl-pyridin-2 - ylamine

According to the process described in Preparation Example 159, was prepared from Example 156 from the chloro compound obtained The title compound as a yellow solid, yield 80%.

¹H NMR(CD ₃OD+TFA-d，400MHz)δ：0.61(t，3H)，1.40(m，2H)，2.40(s，3H)， 3.30(s，3H)，3.36(t，2H)，3.80(t，2H)，4.61(s，2H)，4.84(t，2H)，7.06(d，1H)， 7.92(s，1H)，8.25(d，1H).

Preparation of Example 161

N-[5 - chloro-1 - (2 - ethoxy-ethyl) -3 - methoxy-methyl-1H-pyrazolo [4,3-d] pyrimidine Pyridine -7 - yl] -6 - methyl-pyridin-2 - ylamine

From the chloro compound of Preparation 158 (280mg, 0.73mmol) and sodium methoxide (198mg, 3.67mmol) in methanol (4mL) was stirred at room temperature for 18 hours. Tlc Analysis showed material remaining, so adding additional sodium methoxide (79.2mg, 1.46mmol), The reaction was stirred for an additional 1 hour. Quenched with 10% aqueous citric acid reaction in vacuo The mixture was evaporated. The residue was partitioned between methylene chloride and water, the layers were separated. There will be Phase was washed with 10% aqueous citric acid and water, then dried over magnesium sulfate, evaporated in vacuo Hair. The crude product was purified by column chromatography on silica gel, using dichloromethane: methanol gradient (100:0 To 98:2) to give the title compound as a yellow solid, 190mg. ...

¹H NMR(CDCl ₃，400MHz)δ：1.22(t，3H)，2.46(s，3H)，3.50(s，3H)，3.65(q，2H)， 3.94(t，2H)，4.78(m，4H)，6.87(d，1H)，7.63(t，1H)，8.22(d，1H)，10.05(br s， 1H).LRMS：m/z APCI+377[MH] ⁺

N-[5 - chloro-1 - (2 - ethoxy-ethyl) -3 - methoxy-methyl-1H-pyrazolo [4,3-d] pyrimidine Pyridine -7 - yl] - pyrimidin-4 - yl - amine

The process described in Preparation Example 161, was prepared from from the chloro compound obtained in Example 157 The title compound as a pale yellow solid.

¹H NMR(CD ₃OD，400MHz)δ：1.19(t，3H)，3.44(s，3H)，3.67(q，2H)，3.96(t， 2H)，4.75(s，2H)，4.85(t，2H)，8.44(d，1H)，8.67(d，1H)，8.87(s，1H).

LRMS：m/z APCI+364[MH] ⁺

Preparation of Example 163

N-[5 - chloro-1 - (2 - ethoxy-ethyl) -3 - ethoxy-methyl-1H-pyrazolo [4,3-d] pyrimidine Pyridine -7 - yl] -4 - methyl-pyridin-2 - ylamine

The process described in Preparation Example 159 (but column eluent, ethyl acetate: pentane), from From the chloro compound prepared in Example 155 and sodium ethoxide in ethanol to give the title compound, Off-white solid, yield 70%.

¹H NMR(CD ₃OD，400MHz)δ：1.10(t，3H)，1.21(t，3H)，2.43(s，3H)，3.55-3.68 (m，4H)，3.92(t，2H)，4.76(s，2H)，4.84(t，2H)，6.99(s，1H)，8.19(s，1H)，8.34(s， 1H).LRMS：m/z APCI+391[MH] ⁺

Preparation of Example 164

3 - [1 - (2 - ethoxy-ethyl) -3 - methoxy-7 - (4 - methyl-pyridin-2 - yl amino Yl)-1H-pyrazolo [4,3-d] pyrimidin-5 - yl] -3,8 - diazabicyclo [3.2.1] octane-8 - Acid tert-butyl ester

Preparation Example 159 from a chlorine compound (100mg, 0.27mmol), 3,8 - diaza- Bicyclo [3.2.1] octane-8 - carboxylic acid tert-butyl ester (Tet.Lett.43 (2002) ,899-902) (229mg, 1.08mmol) and N-ethyldiisopropylamine (232μL, 1.33mmol) was dissolved in dimethyl Sulfoxide (3mL), the reaction mixture was sealed in the container was heated to 120 ℃ for 18 hours. The reaction mixture was diluted with dichloromethane, washed with water (x2), 10% aqueous citric acid solution and brine, Polyester. The organic phase was dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to silica gel column chromatography , Eluting with dichloromethane: methanol (100:0 to 95:5) to give the title product.

¹H NMR(CD ₃OD，400MHz)δ：1.11(t，3H)，1.50(s，9H)，1.79(m，2H)，1.92(m， 2H)，2.39(s，3H)，3.14(m，2H)，3.43(s，3H)，3.58(q，2H)，3.87(t，2H)，4.33(m， 2H)，4.39(m，2H)，4.67(m，4H)，6.91(d，1H)，8.13(d，1H)，8.18(s，1H).

LRMS：m/z APCI+553[MH] ⁺

Preparation of Example 165

(1S, 4S) -5 - [1 - (2 - ethoxy-ethyl) -3 - methyl-7 - (5 - methyl-2 - yl amino Yl)-1H-pyrazolo [4,3-d] pyrimidin-5 - yl] -2,5 - diazabicyclo [2.2.1] heptane-2 - Acid tert-butyl ester

Preparation of Example 121 using a chlorine compound and (1S, 4S) -2,5 - diazabicyclo [2.2.1] Heptane-2 - carboxylic acid tert-butyl ester, by means similar to that described in Preparation Example 164 The title product was prepared Thereof.¹H NMR(CD ₃OD，400MHz)δ：1.11(t，3H)，1.39-1.46(s，9H)，2.00(m，2H)，2.28 (s，3H)，2.40(s，3H)，3.43(m，2H)，3.54-3.67(m，4H)，3.85(t，2H)，4.55(m，1H)， 4.62(t，2H)，4.92(m，1H)，7.60(d，1H)，8.08(s，1H)，8.26(m，1H).LRMS：m/z APCI+509[MH] ⁺

Preparation of Example 166

(1S, 4S) -5 - [1 - (2 - ethoxy-ethyl) -3 - methyl-7 - (pyrimidin-4 - ylamino)-1H- Pyrazolo [4,3-d] pyrimidin-5 - yl] -2,5 - diazabicyclo [2.2.1] heptane-2 - carboxylic acid tert-butyl Ester

Preparation Example 72 using a chlorine compound and (1S, 4S) -2,5 - diazabicyclo [2.2.1] Heptane-2 - carboxylic acid tert-butyl ester, by means similar to that described in Preparation Example 164 The title product was prepared Thereof.¹H NMR(CD ₃OD，400MHz)δ：1.22(t，3H)，1.33(2xs，9H)，2.01(m，2H)，2.43(s， 3H)，3.47(m，3H)，3.65(m，4H)，3.91(m，2H)，4.63(t，2H)，5.01(m，1H)，8.35(br s，1H)，8.60(d，1H)，8.80(s，1H).LRMS：m/z APCI+496[MH] ⁺

Preparation Example 167

(1S, 4S) -5 - [1 - (2 - ethoxy-ethyl) -3 - ethoxy-methyl-7 - (pyrimidin-4 - yl amino Yl)-1H-pyrazolo [4,3-d] pyrimidin-5 - yl] -2,5 - diazabicyclo [2.2.1] heptane-2 - Acid tert-butyl ester

In a sealed container, from the chloro compound of Preparation 163 (100mg, 0.26mmol), (1S, 4S) -2,5 - diazabicyclo [2.2.1] heptane-2 - carboxylic acid tert-butyl ester (202.3mg, 1.02mmol) and N-ethyldiisopropylamine (226μL, 1.3mmol) in dimethyl Sulfoxide (3mL) the mixture heated at 120 ℃ for 18 hours. The cooling of the reactants Partitioned between dichloromethane and water, the layers separated, and the organic phase washed with water, then brine, Dried over magnesium sulfate, and evaporated in vacuo. Product was purified by column chromatography through silica gel, using acetic acid Ethyl ester as the eluent, to give the title compound as an orange oil.

¹H NMR(CD ₃OD，400MHz)δ：1.10(t，3H)，1.19(t，3H)，1.40-1.48(2xs，9H)，2.00 (m，2H)，2.40(s，3H)，3.49(m，2H)，3.56-3.71(m，6H)，3.89(t，2H)，4.57(m，1H)， 4.69-4.75(m，4H)，4.95(s，1H)，6.92(d，1H)，8.14(d，1H)，8.34(s，1H).

LRMS：m/z ES+553[MH] ⁺

Preparation of Example 168

N-[5 - ((1R, 4R) -5 - benzyl-2 ,5 - diazabicyclo [2.2.1] hept-2 - yl) -1 - (2 - Ethoxy-ethyl) -3 - methyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-2 - Ylamine

The preparation of a chlorine compound of Example 120 (180mg, 0.52mmol), (1R, 4R) -2 - benzyl- -2,5 - Diazabicyclo [2.2.1] heptane dihydrobromide (EP 400661, Example 8) (545mg, 2.90mmol) and N-ethyldiisopropylamine (723μL, 4.16mmol) was dissolved in dimethyl Sulfoxide (3mL), the reaction mixture was sealed in the container was heated to 120 ℃ for 18 hours. The reaction mixture water (50mL) and ethyl acetate (50mL) was partitioned between aqueous phase was separated, with Ethyl acetate (50mL) was washed. Organic phases were combined, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography through silica gel, using ethyl acetate: methanol (100:0 to 95:5), To obtain the title product 62mg.

¹H NMR(CD ₃OD，400MHz)δ：0.12(t，3H)，1.96(m，1H)，2.09(m，1H)，2.38(s， 3H)，2.42(s，3H)，2.88(m，1H)，3.08(m，1H)，3.59(m，3H)，3.80-3.95(m，7H)， 4.62(m，2H)，6.92(d，1H)，7.35(m，5H)，8.12(d，1H)，8.35(m，1H).LRMS：m/z APCI+499[MH] ⁺

Preparation of Example 169

3 - dimethylamino-azetidin-1 - carboxylic acid tert-butyl ester

In a sealed container, 3 - iodo-azetidin-1 - carboxylic acid tert-butyl ester (EP 1176147, Preparation Example 18) (5g, 17.6mmol) and dimethylamine (27mL, 33% ethanol solution, 176mmol) was heated to 80 ℃ up to 28 hours. The mixture was cooled, evaporated in vacuo Hair, the residue was pre-adsorbed onto silica gel. Then purified by column chromatography through silica gel, using acetic Acetate: hexane (50:50) as the eluent to give the title compound as a yellow oil, 1.07g.¹H NMR(CDCl ₃，400MHz)δ：1.38(s，9H)，2.08(s，6H)，2.94(m，1H)，3.70(m， 2H)，3.84(m，2H).

Preparation of Example 170

3 - dimethylamino azetidine bis (trifluoroacetate)

Prepared from the compound of Example 169 (760mg, 3.79mmol) and trifluoroacetic acid (4mL) In dichloromethane (12mL) was stirred at room temperature for 1 hour. Solution was concentrated in vacuo Solution, the residue azeotroped with toluene and methylene chloride. The product was triturated with ethyl acetate, filtered The resulting solid was dried to give the title compound 600mg.

¹H NMR(CD ₃OD，400MHz)δ：2.80(s，6H)，4.23(m，1H)，4.34(m，2H)，4.45(m， 2H).

Preparation of Example 171

N-[5 - chloro-3 - methyl-1 - (2 - ethyl-propoxy)-1H-pyrazolo [4,3-d] pyrimidin-7 - Yl] -6 - methyl-pyridin-2 - ylamine

Bis (trimethylsilyl) amide sodium (1.43g, 7.8mmol) was added portionwise and 2 - amino -6 - methyl-pyridine (421.7mg, 3.9mmol) in tetrahydrofuran (7mL) solution, and the solution Then stirred for 10 minutes. Was added dropwise from the chloro compound prepared in Example 62 (750mg, 2.6mmol) In tetrahydrofuran (7mL) was added and the reaction was stirred at room temperature for 2 hours. Saturated chlorinated dropping Aqueous solution of ammonium, and the mixture was extracted with methylene chloride. The organic solution was washed with water and brine, Then dried over magnesium sulfate, and evaporated in vacuo. From the product was recrystallized from isopropyl acetate, To give the title compound as an off-white solid.

¹H NMR(CDCl ₃，400MHz)δ：0.79(t，3H)，1.69(m，2H)，2.46(s，3H)，2.55(s， 3H)，3.56(t，2H)，3.93(t，2H)，4.72(t，2H)，6.88(d，1H)，7.64(m，1H)，8.23(d， 1H)，9.94(s，1H).LRMS：m/z APCI+361[MH] ⁺

Preparation of Example 172

N-{5 - chloro-3 - methyl-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} pyrimidin-4 - yl amine

Bis (trimethylsilyl) amide sodium (1.46g, 7.99mmol) was added portionwise to 4 - Amino-pyrimidine (864mg, 8.0mmol) in tetrahydrofuran (10mL) solution, the solution is then stirred Mix for 15 minutes. Was added dropwise from the chloro compound prepared in Example 130 (1.17g, 4.0mmol) of the four Tetrahydrofuran (10mL) was added and the reaction was stirred at room temperature for 2 hours. In acetic acid mixture Ethyl (50mL) and water (100mL) allocated between the layers were separated. The aqueous phase with ethyl acetate (100mL) Extract the combined organic solution was dried over magnesium sulfate, and evaporated in vacuo. The crude product through silica Gel column chromatography, using ethyl acetate as the eluent, and the resulting solid was triturated with ether to give The title compound as a yellow solid, 1.02g. ...

¹H NMR(CDCl ₃，400MHz)δ：2.50(s，3H)，4.00-4.10(m，2H)，4.12(t，2H)，4.85(t， 2H)，8.40(d，1H)，8.60(d，1H)，8.85(s，1H).LRMS：m/z APCI+410[MNa] ⁺

3 - (methoxycarbonyl)-4 - nitro-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazol -5 - carboxylic acid

The isopropyl azodicarboxylate (71.9mL, 366mmol) in tetrahydrofuran (80mL) was dissolved Was added dropwise 4 - nitro-pyrazol-3, 5 - dicarboxylic acid methyl ester (60g, 260mmol) and triphenyl phosphine (96.15g, 366mmol) in tetrahydrofuran (650mL) solution while stirring under nitrogen, through the Over cooled in an ice bath while maintaining the reaction temperature between 0 ℃ and 10 ℃. After adding completely, the Mixture was warmed to room temperature, stirred for 2 days. The solvent was removed under reduced pressure, the residue was dissolved in methyl Alcohol (800mL), cooled to 0 ℃. Was added at 0 ℃ of potassium hydroxide (16.16g, 288mmol) In methanol (200mL) solution, the reaction was warmed to room temperature, stirred for 16 hours. In vacuo The solvent was removed and the residue water (600mL) and ethyl acetate (600mL) partitioned between. The water Layer is washed with ethyl acetate (2 × 200mL), the organic phase is washed with hydrochloric acid to pH 1. Aqueous solution Extracted with ethyl acetate (3 × 400mL), the extracts were combined, dried over sodium sulfate, the true Air concentrated to give the title compound as a colorless solid, 52.86g, 59%. ...

¹H NMR(CDCl ₃，400MHz)δ：3.77(q，2H)，3.93(s，3H)，4.00(t，2H)，4.84(t，2H).

3 - ethyl-4 - nitro-1 - (2,2,2 - trifluoro-ethoxy)-ethyl pyrazole-5 - carboxamide

The isopropyl azodicarboxylate (53.74g, 266mmol) in tetrahydrofuran (50mL) solution Droplets added to 3 - ethyl-4 - nitro-pyrazole-5 - carboxamide (EP 1176142, pg 18) (35.0g, 190mmol) and triphenylphosphine (69.79g, 266mmol) in tetrahydrofuran (450mL) solution, with While stirring under nitrogen, cooled in an ice bath while keeping the reaction temperature between 0 ℃ and 10 ℃. Adding complete, the mixture was stirred for 2 hours, then warmed to room temperature. Removed in vacuo Solvent, the residue was recrystallized from hot isopropanol twice to give the title compound as a colorless Solid, 49.06g.

¹H NMR(CDCl ₃，400MHz)δ：1.25(t，3H)，2.92(q，2H)，3.78(q，2H)，3.98(t， 2H)，4.56(t，2H)，5.95(br s，1H)，7.11(br s，1H).

Preparation of Example 175

5 - (carbamoyl) -4 - nitro -1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazole 3 - carboxylic acid methyl ester

20 ℃ under nitrogen and the acid from Preparation 173 (70.0g, 204mmol) was dissolved in Chloride (1000mL) and N, N-dimethylformamide (1mL) mixtures thereof. Added oxalyl chloride (25mL, 366mmol), while stirring. The mixture was stirred for 16 hours and then in vacuo Concentrated, and the residue azeotroped with dichloromethane (3 × 200mL). The residue was dissolved in tetrahydrofuran (1000mL), cooled to -78 ℃, was added dropwise 0.88 ammonia (70mL), while maintaining the mixture at -78 ℃. Adding complete, the mixture was stirred for 1 hour and then was added at -78 ℃ excess Hydrochloric acid (to obtain pH 1). The mixture was warmed to room temperature, the solvent was removed in vacuo. Filter The resulting cream colored solid was collected, washed with water (3 × 100mL). The solid was washed with diethyl ether and methanol Mixture (20:1,20 mL / g) developed to give the title compound as a colorless solid, 40.0g. ...

¹H NMR(CDCl ₃，400MHz)δ：3.78(q，2H)，3.95(s，3H)，3.98(t，2H)，4.76(t，2H)， 5.91(br s，1H)，7.03(br s，1H).

4 - Amino - 3 - ethyl-1 - (2,2,2 - trifluoro-ethoxy)-ethyl pyrazole-5 - carboxamide

Prepared from the compound of Example 174 (23.34g, 75mmol) in methanol (400mL) was At 300kPa and 50 ℃ using 10% palladium carbon (6.0g) hydrogenated for 2 hours. Add another 2.0g Catalyst, the hydrogenation was continued another 14 hours. The hot solution was filtered through Arbocel  cake Washed with methanol (4 × 100mL). The filtrate was concentrated in vacuo, the residue was mixed with toluene (100mL) Azeotropic distillation to give the title compound as a red oil, 19.06g.

¹H NMR(CDCl ₃，400MHz)δ：1.21(t，3H)，2.55(q，2H)，3.16(br s，2H)，3.79(q， 2H)，3.99(t，2H)，4.61(t，2H)，

Preparation of Example 177

4 - amino-5 - carbamoyl -1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazole 3 - carboxylic acid methyl ester

Prepared from the compound of Example 175 (40.0g, 118mmol) in methanol (640mL) was At 300kPa and 50 ℃ using 10% palladium carbon (10.0g) hydrogenated for 3 hours. The hot solution was passed through Arbocel  filtered and the cake washed with dichloromethane. The filtrate was concentrated in vacuo to give the title Compound as an off-white solid, 34.2g.

¹H NMR(CDCl ₃，400MHz)δ：3.80(q，2H)，3.91(s，3H)，4.07(t，2H)，4.63(t，2H)， 6.29(br s，2H).

Preparation of Example 178

3 - ethyl-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl] -1,4 - dihydro-pyrazolo [4,3-d] Pyrimidine-5, 7 - dione

Under nitrogen, prepared from the compound of Example 176 (19.06g, 68.0mmol) in acetonitrile (150mL) was added dropwise to 2 hours after a stirred solution of N, N-carbonyldiimidazole (16.55g, 100mmol) in refluxing acetonitrile (850mL) in a solution. The mixture was heated under reflux for 2 hours, cooled, the solvent was removed in vacuo. The residue was washed with water (150mL) developed by filtration The resulting colorless solid was washed with water (100mL) dried at 80 ℃ dried in vacuo to give the title Compound 17.53g.

¹H NMR(CDCl ₃，400MHz)δ：1.26(t，3H)，2.67(q，2H)，3.78(q，2H)，4.00(t，2H)， 4.63(t，2H)，7.94(br s，1H)，8.43(br s，1H).LRMS：m/z ES-305[M-H] ^-

Preparation Example 179

5,7 - dioxo-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl] -4,5,6,7 - tetrahydro-1H- Pyrazolo [4,3-d] pyrimidine-3 - carboxylic acid methyl ester

Under nitrogen, prepared from the compound of Example 177 (21.7g, 70.0mmol) in acetonitrile (150mL) was added dropwise to 2 hours after a stirred solution of N, N-carbonyldiimidazole (17.02g, 105mmol) in refluxing acetonitrile (850mL) in a solution. The mixture was heated under reflux for 2 hours, cooled, the solvent was removed in vacuo. The residue was washed with water (150mL) developed by filtration The resulting pale gray solid was washed with water (3 × 100mL), dried in vacuo at 80 ℃ to give The title compound 21.26g.

¹H NMR(CDCl ₃，400MHz)δ：3.79(q，2H)，3.98(s，3H)，4.07(t，2H)，4.77(t，2H)， 7.87(br s，1H)，8.41(br s，1H).LRMS：m/z ES-335[M-H] ^-

Preparation of Example 180

5,7 - dichloro-3 - ethyl-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidine

Phosphorus oxychloride (22.8mL, 0.24mol) was added to diketone from Preparation Example 178 (5g, 16mmol) and tetraethylammonium chloride (8.11g, 48mmol) in propionitrile (75mL) suspension, the mixing Compound at 106 ℃ stirred for 18 hours. The mixture was cooled, concentrated in vacuo, and the residue Azeotroped with toluene (2 × 50mL). The residual oil was dissolved in ethyl acetate (50mL), washed with water (200mL) , Dried over magnesium sulfate, and evaporated in vacuo to give the title compound 4.98g.

¹H NMR(CDCl ₃，400MHz)δ：1.40(t，3H)，3.05(q，2H)，3.70(q，2H)，4.05(t，2H)， 4.90(t，2H).

Preparation of Example 181

5,7 - dichloro-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidine -3 - carboxylic acid methyl ester

Phosphorus oxychloride (56mL, 0.60mol) was added to diketone from Preparation Example 179 (13.5g, 40mmol) and tetraethylammonium chloride (20.0g, 120mmol) in propionitrile (150mL) suspension of the The mixture was stirred under reflux for 18 hours. The mixture was cooled, concentrated in vacuo, and the residue Azeotroped with toluene (2 × 50mL). The residue in dichloromethane (500mL) and water (500mL) of Distribution among the layers were separated, the aqueous layer with additional methylene chloride (500mL) was extracted. The combined organic solution Washed with water (200mL), brine (100mL), dried over magnesium sulfate, and evaporated in vacuo. The crude product was purified by column chromatography on silica gel, using ethyl acetate: pentane gradient elution (34:66 to 50:50) to give the title compound as a white solid, 9.4g. ...

¹H NMR(CDCl ₃，400MHz)δ：3.75(q，2H)，4.10(m，5H)，5.05(t，2H).

{5,7 - dichloro-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] Pyrimidin-3 - yl} methanol

The diisobutyl aluminum hydride (33.2mL, 1M solution in tetrahydrofuran, 33.2mmol) was added dropwise Cooled (-78 ℃) prepared from the ester of Example 181 (3.1g, 8.31mmol) in tetrahydrofuran (50mL) solution, to maintain the temperature below -70 ℃. Once inserted fully, then the reactants up Warm to -10 ℃, stirred for 1 hour. Tlc analysis showed material remaining, so the reaction was re- New cooled to -78 ℃, adding additional diisobutyl aluminum hydride (8.3mL, 1M solution in tetrahydrofuran Solution, 8.3mmol), and the reaction was again warmed to -10 ℃, stirred for another 20 minutes. The anti- Should was again cooled to -78 ℃, adding hydrochloric acid (2M, 30mL), and the mixture was warmed to room temperature, For 18 hours. The mixture was diluted with water, extracted with dichloromethane (2x). The combined organic solution Washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The crude product through silica Gel column chromatography eluting with dichloromethane: methanol gradient (100:0 to 97:3) to give the title Compound as an orange oil, 2.22g. ...

¹H NMR(CDCl ₃，400MHz)δ：2.69(s，1H)，3.75(q，2H)，4.08(t，2H)，4.91(t，2H)， 5.09(s，2H).LRMS：m/z APCI+345[MH] ⁺

5 - {5 - chloro -3 - (hydroxymethyl) -1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl amino}-1 - methyl-1H-pyridin-2 - one

5 - {5 - chloro -3 - (hydroxymethyl) -1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl amino}-1 - methyl-1H-pyridin-2 - one...

¹H NMR(DMSO-d ₆，400MHz)δ：3.45(s，3H)，3.92(t，2H)，4.01(q，2H)，4.13(d， 2H)，4.87(t，2H)，5.24(m，1H)，6.46(d，1H)，7.51(m，1H)，7.81(d，1H)，8.81(s， 1H).LRMS：m/z APCI+433[MH] ⁺

5 - chloro-7 - (6 - methyl-pyridin-2 - yl-amino) -1 - [2 - (2,2,2 - trifluoro-ethoxy) ethyl Yl]-1H-pyrazolo [4,3-d] pyrimidine-3 - carboxylic acid methyl ester

Prepared from the compound of Example 181 in dichloromethane (2g, 5.36mmol) with a 2 - amino-6 - methyl Pyridine (1.74g, 16.1mmol) in acetonitrile (15mL) was stirred at reflux under heating for 5 Hours. The mixture was cooled in an ice bath, washed with 10% citric acid solution (12mL) diluted with the Mixture was stirred for 15 minutes. The resulting precipitate was filtered off, washed with acetonitrile: water (50:50,10 mL) Washed and dried to give the title compound as a pale pink solid, 1.8g.

¹H NMR(DMSO-d ₆+TFA-d，400MHz)δ：2.59(s，3H)，3.90(s，3H)，4.10(m，4H)， 5.15(t，2H)，7.05(d，1H)，7.90(m，1H)，8.02(d，1H).

Preparation Example 185

5 - chloro-7 - (4 - methyl-pyridin-2 - yl-amino) -1 - [2 - (2,2,2 - trifluoro-ethoxy) ethyl Yl]-1H-pyrazolo [4,3-d] pyrimidine-3 - carboxylic acid methyl ester

The process described in Preparation Example 184, was prepared from Example 181 from the compound obtained in methylene The title compound as a pale yellow solid.

¹H NMR(DMSO-d ₆+TFAd，400MHz)δ：2.50(s，3H)，3.90(s，3H)，4.00-4.10(m， 4H)，5.05(t，2H)，7.08(d，1H)，7.79(s，1H)，8.25(d，1H).LRMS：m/z APCI+445 [MH] ⁺

Preparation of Example 186

{5 - chloro-7 - (6 - methyl-pyridin-2 - yl-amino) -1 - [2 - (2,2,2 - trifluoro-ethoxy) ethyl Yl]-1H-pyrazolo [4,3-d] pyrimidin-3 - yl} methanol

The diisobutyl aluminum hydride (7mL, 1M solution in tetrahydrofuran, 7mmol) was added to the cooling (-10 ℃) prepared from the ester of Example 184 (1.2g, 2.7mmol) in tetrahydrofuran (25mL) was dissolved Solution, and the reaction was stirred at -10 ℃ for 1 hour, followed by stirring at 0 ℃ for 1 hour. TLC analysis showed the remaining raw materials, thus adding additional diisobutyl aluminum hydride (5.4mL, 1M Solution in tetrahydrofuran, 5.4mmol), the reaction was stirred for 10 minutes at 10 ℃. The reaction Was cooled to -5 ℃, adding hydrochloric acid (1N, 50mL), the mixture was poured into additional hydrochloric acid (2N, 50mL) in. The mixture was stirred for 30 minutes and then extracted with dichloromethane (total 300mL) And dichloromethane: methanol (95:5 by volume, 3 × 200mL) was extracted and the combined organic extracts were Dried over magnesium sulfate, and evaporated in vacuo. The product was triturated with diethyl ether and sonicated, in the real The resulting solid was air dried to give the title compound as a yellow powder, 760mg. ...

¹H NMR(CD ₃OD，400MHz)δ：2.70(s，3H)，3.95(q，2H)，4.10(t，2H)，4.85(s， 2H)，5.05(t，2H)，7.40(d，1H)，7.98(s，1H)，8.30(m，1H).

{5 - chloro-7 - (4 - methyl-pyridin-2 - yl-amino) -1 - [2 - (2,2,2 - trifluoro-ethoxy) ethyl Yl]-1H-pyrazolo [4,3-d] pyrimidin-3 - yl} methanol

Prepared according to the procedure similar to that described in Example 186, Example 185 was prepared from the compound from The title compound was prepared 92% yield as a pink solid.

¹H NMR(CD ₃OD，400MHz)δ：2.52(s，3H)，3.98(q，2H)，4.10(t，2H)，4.85(s， 2H)，5.00(t，2H)，7.19(d，1H)，7.82(s，1H)，8.21(d，1H).

Preparation of Example 188

N-{5 - chloro-3 - (chloromethyl) -1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -6 - methyl-pyridin-2 - ylamine

Thionyl chloride (0.3mL, 3.84mmol) was added to the alcohol from the preparation of Example 186 (400mg, 0.96mmol) in dichloromethane (6mL) solution, and the reaction was stirred for 10 minutes. In vacuo The reaction mixture was concentrated, the residue azeotroped with dichloromethane (3 × 10mL), to give the title Thereof.

LRMS：m/z APCI+435[MH] ⁺

Preparation of Example 189

N-{5 - chloro-3 - (chloromethyl) -1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -4 - methyl-pyridin-2 - ylamine

The process described in Preparation Example 188, Example 187 was prepared from the alcohol from the title compound Thereof.

LRMS：m/z APCI+435[MH] ⁺

Preparation of Example 190

5 - {5 - chloro -3 - (chloromethyl) -1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl amino}-1 - methyl-1H-pyridin-2 - one

The process described in Preparation Example 188, Example 183 was prepared from the alcohol from the title compound Thing as an off white solid.

LRMS：m/z APCI+451[MH] ⁺

Preparation of Example 191

N-{5 - chloro-3 - methoxy-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazol Triazolo [4,3-d] pyrimidin-7 - yl} -6 - methyl-pyridin-2 - ylamine

Preparation Example 188 from the chloride (100mg, 0.23mmol), sodium methoxide (25-30% Methanol solution, 0.2mL, 0.91mmol) and sodium iodide (10mg) in tetrahydrofuran (1mL) in The mixture was stirred at room temperature for 30 minutes. The mixture was diluted with 10% citric acid solution, with two Methylene chloride extracts (3 × 100mL). The organic extracts were combined, dried over magnesium sulfate in vacuo Evaporated. The crude product was purified by column chromatography on silica gel, using dichloromethane: methanol (99:1) as the wash Degreasing agent, to obtain the title compound.

LRMS：m/z APCI+431[MH] ⁺

Preparation 192-195

The process described in Preparation Example 191, was prepared from the appropriate dichloro compound of Example 188-190 Following compounds were prepared.

a-developed with ether / sonication and isolation of the product, have not been purified by column chromatography.

b-in the absence of the presence of catalytic NaI, with methanol as the solvent for 18 hours.

Preparation of Example 196

N-[5 - chloro-1 - (2 - ethoxy-ethyl) -3 - ethoxy-methyl-1H-pyrazolo [4,3-d] pyrimidine Pyridine -7 - yl] -6 - methyl-pyridin-2 - ylamine

Sodium ethoxide (1.15mL, 21% wt / vol ethanol solution, 5.25mmol) was added to from The compound of Preparation 158 (500mg, 1.31mmol) in ethanol (50mL) solution, and the reaction Was stirred at room temperature for 18 hours. Saturated ammonium chloride (50mL), ethanol was removed in vacuo. The aqueous residue was washed with water (10mL) diluted with ethyl acetate (70mL) was extracted. The organic solution was Dried over magnesium sulfate, and concentrated in vacuo to give the title compound 420mg.

¹H NMR(CDCl ₃，400MHz)δ：1.16(t，3H)，1.22(t，3H)，2.49(s，3H)，3.65(q，4H)， 3.95(t，2H)，4.78(s，2H)，4.85(m，2H)，7.02(d，1H)，7.75(m，1H)，8.29(d，1H).

LRMS：m/z APCI+391[MH] ⁺

Preparation of Example 197

N-{5 - chloro-3 - methyl-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -6 - methyl-4 - yl amine

Bis (trimethylsilyl) amide sodium (917mg, 15mmol) was added to prepared from Amine of Example 133 (300mg, 2.25mmol) in tetrahydrofuran (30mL) suspension, whilst ice-cooling. The mixture was stirred for 10 minutes and then the compound from Preparative Example 130 (822mg, 2.5mmol), and the reaction was stirred at 0 ℃ for 1 hour. Citric acid solution (5mL), in The mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate (150mL) and water (100mL) of between With the layers were separated, and the organic phase was dried over magnesium sulfate, and evaporated in vacuo to give the title Compound as a pale yellow solid, 968mg.

¹H NMR(DMSO-d ₆+TFA-d，400MHz)δ：2.48(s，3H)，2.57(s，3H)，3.84-3.94(m， 4H)，4.73(t，2H)，7.85(s，1H)，9.08(s，1H).

LRMS：m/z APCI+402[MH] ⁺

Preparation of Example 198

N-{5 - chloro-3 - methyl-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -2 - methyl-pyrimidin-4 - yl amine

The process described in Preparation Example 197, from the compound from Preparative Example 130 and 4 - amino- -2 - Methyl-pyrimidine (J.Het.Chem.14; 1413; 197) to give the title compound, yield, 98%, as a white solid.

¹H NMR(DMSO-d ₆+TFA-d，400MHz)δ：2.50(s，3H)，2.64(s，3H)，3.85-3.90(m， 4H)，4.78(t，2H)，7.90(d，1H)，8.78(d，1H).LRMS：m/z APCI+402[MH] ⁺

Preparation of Example 199

N-{5 - Chloro-3 - ethyl-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -2 - methyl-pyrimidin-4 - yl amine

Bis (trimethylsilyl) amide sodium (740mg, 4.06mmol) in tetrahydrofuran (10mL) was added dropwise 4 - amino -2 - methyl-pyrimidine (J.Het.Chem.14; 1413; 197) (445mg, 4.06mmol) in tetrahydrofuran (10mL) suspension, whilst ice-cooling. The mixture After stirring for 15 minutes, and then the compound from Preparative Example 180 (700mg, 2.04mmol) In tetrahydrofuran (10mL) was added and the reaction was stirred at room temperature for 1 hour. The mixture was 10% citric acid solution (100mL) and ethyl acetate (100mL) allocated between the layers were separated. There will be Phase was washed with water (100mL) and brine (100mL), then dried over magnesium sulfate in vacuo And evaporated to give the title compound as a yellow solid, 880mg.

¹H NMR(CD ₃OD，400MHz)δ：1.37(t，3H)，2.60(s，3H)，2.96(q，2H)，4.06(q， 2H)，4.13(t，2H)，4.86(m，2H)，8.20(m，1H)，8.55(m，1H).LRMS：m/z APCI- 414[M-H] ^-

Preparation of Example 200

N-{5 - Chloro-3 - ethyl-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -6 - methyl-4 - yl amine

The process described in Preparation Example 199, was prepared from Example 133 and 180 from the compound obtained The title compound as a pale yellow solid.

¹H NMR(CD ₃OD，400MHz)δ：1.27(t，3H)，2.45(s，3H)，2.85(q，2H)，3.94(q， 2H)，4.01(t，2H)，4.86(m，2H)，8.18(m，1H)，8.61(m，1H).LRMS：m/z APCI- 414[M-H] ^-

Preparation of Example 201

N-{5 - Chloro-3 - ethyl-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} pyridazin-4 - yl amine

Prepared according to the procedure similar to that described in Example 199, Example 180 was prepared from the compound from And 4 - amino-pyridazine (J.Het.Chem.19; 1285; 1982) to give the title compound, close 64%, but in this process, the compound was purified by column chromatography through silica gel, using dichloromethane : Methanol (90:10) as eluent.

¹H NMR(CD ₃OD，400MHz)δ：1.37(t，3H)，2.96(q，2H)，3.96(q，2H)，4.06(t， 2H)，4.95(t，2H)，8.31(m，1H)，9.01(m，1H)，9.42(m，1H).LRMS：m/z APCI+ 403[MH] ⁺

Preparation of Example 202

N-{5 - Chloro-3 - ethyl-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} pyrimidin-4 - yl amine

N-{5 - Chloro-3 - ethyl-1 - [2 - (2,2,2 - trifluoro-ethoxy)-ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} pyrimidin-4 - yl amine...

¹H NMR(CDCl ₃，400MHz)δ：1.40(t，3H)，3.00(q，2H)，4.05(q，2H)，4.20(t，2H)， 4.80(t，2H)，8.40(m，1H)，8.70(dd，1H)，8.90(s，1H)，9.55(br s，1H).LRMS：m/z

APCI+403[MH] ⁺

1 - {3 - methyl-7 - (4 - methyl-pyridin-2 - yl-amino) -1 - [2 - (2,2,2 - trifluoroethoxy) Ethyl]-1H-pyrazolo [4,3-d] pyrimidin-5 - yl} piperidin-4 - carboxylic acid ethyl ester

1 - {3 - methyl-7 - (4 - methyl-pyridin-2 - yl-amino) -1 - [2 - (2,2,2 - trifluoroethoxy) Ethyl]-1H-pyrazolo [4,3-d] pyrimidin-5 - yl} piperidin-4 - carboxylic acid ethyl ester...

¹H NMR(CD ₃OD，400MHz)δ：1.25(t，3H)，1.70(m，2H)，1.95(m，2H)，2.38(s， 3H)，2.40(s，3H)，2.62(m，1H)，3.10(m，2H)，4.00(q，2H)，4.06(t，2H)，4.12(q， 2H)，4.60(m，2H)，4.71(m，2H)，6.93(d，1H)，8.14(d，1H)，8.20(m，1H).

LRMS：m/z APCI+522[MH] ⁺

The compounds of the invention are cyclic guanosine monophosphate monophosphate (cGMP) - specific phosphodiesterase type 5 Inhibitor (PDE-5 inhibitors). Suitable for the present invention, preferred compounds are potent selection Selective PDE-5 inhibitors. For cyclic guanosine 3 ', 5'-monophosphate (cGMP) and cyclic adenosine 3', 5'- Monophosphate (cAMP) phosphodiesterase PDE inhibitory activity in vitro can make use of their IC₅₀Value (50% inhibition of enzyme activity concentration of compound required) measurement to measurement.

Required PDE enzymes can be isolated from a variety of sources, including human corpus cavernosum, human and rabbit platelets, Heart chamber, human skeletal muscle and bovine retina, the method is essentially adapted from Thompson, W J et al.; Biochemistry 18 (23) ,5228-5237, 1979 described methods, such as Ballard SA et al.; J.Urology 159 (6) ,2164-2171, 1998 described above. The exact terms, cGMP-specific PDE-5 and cGMP-inhibited cAMP PDE-3 from human Cavernous tissue, human platelets or rabbit platelets obtained; cGMP-stimulated PDE-2 from the sea Cotton body obtained; calcium / calmodulin (Ca / CAM) - dependent PDE-1 was obtained from the heart chamber; cAMP-specific PDE-4 is obtained from human skeletal muscle; photoreceptor PDE-6 from bovine retina Film obtained. 7-11 phosphodiesterase from SF9 cells transfected to human recombinant full-length Cloned. ...

Required PDE enzymes can be isolated from a variety of sources, including human corpus cavernosum, human and rabbit platelets, Heart chamber, human skeletal muscle and bovine retina, the method is essentially adapted from Thompson, W J et al.; Biochemistry 18 (23) ,5228-5237, 1979 described methods, such as Ballard SA et al.; J.Urology 159 (6) ,2164-2171, 1998 described above. The exact terms, cGMP-specific PDE-5 and cGMP-inhibited cAMP PDE-3 from human Cavernous tissue, human platelets or rabbit platelets obtained; cGMP-stimulated PDE-2 from the sea Cotton body obtained; calcium / calmodulin (Ca / CAM) - dependent PDE-1 was obtained from the heart chamber; cAMP-specific PDE-4 is obtained from human skeletal muscle; photoreceptor PDE-6 from bovine retina Film obtained. 7-11 phosphodiesterase from SF9 cells transfected to human recombinant full-length Cloned. ...³H] - labeled AMP / GMP approximation scintillation measurement method, Uses such as Amersham plc (product code TRKQ7090/7100) improvement of the program. All in all, it flashes approximation assay, the concentration of inhibitor and by low levels of different Substrate (cGMP or cAMP, unlabeled and [³H] - labeled ratio of 3:1, the concentration of ~ 1/3K_mOr less) in the presence of, for IC₅₀≈K _i, Whereby a fixed amount of enzyme was measured to study the PDE Effectiveness of the inhibitor. A final assay volume of assay buffer (20mM Tris-HCl pH 7.4, 5mM MgCl₂, 1mg/mL bovine serum albumin) complement to 100μL. Enzyme to initiate the reaction, the Incubated at 30 ℃ for 30-60 minutes, get in the end matter conversion rate <30%, with 50μL yttrium silicate SPA Beads terminate the reaction (for PDE 9 and 11, the corresponding unlabeled containing 3mM cyclic nucleotides). The plates were re-sealed and shaken for 20 minutes and then in the dark the beads to settle for 30 minutes and then After TopCount plate reader (Packard, Meriden, CT) on the count. The radiation No inhibition of the unit into the control group (100%)% activity, and the inhibitor concentration plotted, Li With 'Fit Curve'Microsoft Excel expanded version to get inhibitor IC₅₀Values.

All compounds of the present invention, PDE-5 of less than 10,000 nM activity. Representative Preferred compounds of the IC₅₀Values listed in the following table.

Example	IC ₅₀(nM)	Example	IC ₅₀(nM)
Example	IC ₅₀(nM)	Example	IC ₅₀(nM)	2	0.50	211	2.7
11	0.31	224	0.2	2	0.50	211	2.7
11	0.31	224	0.2	15	0.11	247	0.47
20	0.64	248	0.30	15	0.11	247	0.47
20	0.64	248	0.30	23	0.47	249	0.16
91	22.6	250	2.37	23	0.47	249	0.16
91	22.6	250	2.37	138	0.33	251	0.25
141	0.15	252	2.81	138	0.33	251	0.25
141	0.15	252	2.81	161	0.5	253	1.20
162	0.24	255	1.43	161	0.5	253	1.20
162	0.24	255	1.43	181	0.41	256	3.89
184	2.94	258	1.99	181	0.41	256	3.89
184	2.94	258	1.99	185	1.32	261	0.57
191	2.4	262	0.93	185	1.32	261	0.57
191	2.4	262	0.93	193	1.01	263	0.27

Claims

1, formula (I) compound

Among

R ¹Is selected from R^A、R ^B、R ^CAnd R^DA cyclic group, each of which optionally substituted by one or more R⁷Groups;

R ²Is hydrogen or C₁-C ₂Alkyl group;

R ³And R⁴Each independently C₁-C ₈Alkyl, C₂-C ₈Alkenyl, C₂-C ₈Alkynyl group or a C₃-C ₁₀Cycloalkyl group, They are each optionally substituted by one or more R⁸Substituted, or R^E, Optionally substituted by one Or more R⁹Substituted, or hydrogen;

Or-NR³R ⁴Constitute R^F, Optionally substituted by one or more R¹⁰Groups;

R ⁵Is a C₁-C ₆Alkyl, C₁-C ₆Haloalkyl, C₂-C ₆Alkenyl, C₂-C ₆Alkynyl group or a C₃-C ₇Cycloalkyl group, They are each optionally substituted by one or more groups selected from hydroxy, C₁-C ₆Alkoxy, C₁-C ₆Haloalkoxycarbonyl Group, C₃-C ₇Cycloalkyl and C₃-C ₇Ring substituted alkoxy group, or a hydrogen;

R ⁶Can be connected to the N¹Or N², Which is R^6AOr hydrogen;

R ^6AIs a C₁-C ₆Alkyl, C₁-C ₆Haloalkyl, C₂-C ₆Alkenyl or C₂-C ₆Alkynyl, each of which Optionally substituted by C₁-C ₆Alkoxy, (C₃-C ₆Cycloalkyl) C₁-C ₆Alkoxy, C₁-C ₆Haloalkoxy or Is selected from R^J、R ^K、R ^LAnd R^MSubstituted cyclic group, or R^6AIs R^N、C ₃-C ₇Cycloalkyl or C₃-C ₇Halogenated cycloalkyl, each of which is optionally substituted C₁-C ₆Alkoxy or C₁-C ₆Haloalkoxy Substituted;

R ⁷Is halo, C₁-C ₆Alkyl, C₁-C ₆Haloalkyl, C₂-C ₆Alkenyl, C₂-C ₆Alkynyl, C₃-C ₁₀Cycloalkyl, C₃-C ₁₀Halogenated cycloalkyl group, an oxo group, a phenyl group, OR¹²、OC(O)R ¹²、NO ₂、NR ¹²R ¹³、 NR ¹²C(O)R ¹³、NR ¹²CO ₂R ¹⁴、C(O)R ¹²、CO ₂R ¹²、CONR ¹²R ¹³Or CN;

R ⁸Is halo, phenyl, C₁-C ₆Alkoxyphenyl, OR¹²、OC(O)R ¹²、NO ₂、NR ¹²R ¹³、 NR ¹²C(O)R ¹³、NR ¹²CO ₂R ¹⁴、C(O)R ¹²、CO ₂R ¹²、CONR ¹²R ¹³、CN、C ₃-C ₆Cycloalkyl group, R^GOr R^H, The latter two optionally substituted by one or more R⁹Groups;

R ⁹Is a C₁-C ₆Alkyl, C₁-C ₆Haloalkyl or CO₂R ¹²；

R ¹⁰Is halo, C₃-C ₁₀Cycloalkyl, C₃-C ₁₀Halogenated cycloalkyl, phenyl, OR¹²、OC(O)R ¹²、 NO ₂、NR ¹²R ¹³、NR ¹²C(O)R ¹³、NR ¹²CO ₂R ¹⁴、C(O)R ¹²、CO ₂R ¹³、CONR ¹²R ¹³, CN, Oxo groups, C₁-C ₆Alkyl or C₁-C ₆Haloalkyl group, the latter two optionally substituted by R¹¹Substituted;

R ¹¹Is OH, phenyl, NR¹²R ¹³Or NR¹²CO ₂R ¹⁴；

R ¹²And R¹³Each independently are hydrogen, C₁-C ₆Alkyl or C₁-C ₆Haloalkyl;

R ¹⁴Is a C₁-C ₆Alkyl or C₁-C ₆Haloalkyl;

R ^AAnd R^JEach independently C₃-C ₁₀Cycloalkyl or C₃-C ₁₀Cycloalkenyl, each of which may be a single Ring, or when there is an appropriate number of ring atoms is polycyclic, and they can be fused to

(a) a monocyclic aromatic ring selected from benzene ring and containing up to three heteroatoms selected from nitrogen, oxygen and sulfur Atoms, a 5 - or 6 - membered heteroaromatic ring, or

(b) containing up to three heteroatoms selected from nitrogen, oxygen and sulfur hetero-atom a 5 -, 6 - or 7 - membered heteroaliphatic Ring;

R ^BAnd R^KAre each independently phenyl or naphthyl, each of which may be fused to

(a)C ₅-C ₇Cycloalkyl or C₅-C ₇Cycloalkenyl ring,

(b) containing up to three heteroatoms selected from nitrogen, oxygen and sulfur hetero-atom a 5 -, 6 - or 7 - membered heteroaliphatic Ring, or

(c) containing up to three heteroatoms selected from nitrogen, oxygen and sulfur hetero-atom a 5 - or 6 - membered heteroaromatic ring; R^C、R ^LAnd R^NAre each independently a monocyclic or when there is an appropriate number of ring atoms is more Ring, saturated or partially unsaturated ring system containing from 3 to 10 ring atoms, of which at At least one selected from nitrogen, oxygen and sulfur hetero-atoms, which ring may be fused to the C₅-C ₇Cycloalkyl or C₅-C ₇Or a cycloalkenyl group selected from a monocyclic aromatic ring: a benzene ring containing up to three substituents selected from Nitrogen, oxygen and sulfur hetero atom a 5 - or 6 - membered heteroaromatic ring;

R ^DAnd R^MEach independently contain up to three independently selected from nitrogen, oxygen and sulfur hetero-atoms, 5 - Or 6 - membered heteroaromatic ring which may be further fused to

(a) the second containing up to three heteroatoms selected from nitrogen, oxygen and sulfur hetero-atom a 5 - or 6 - membered heteroaryl Aromatic ring,

(b)C ₅-C ₇Cycloalkyl or C₅-C ₇Cycloalkenyl ring,

(c) containing up to three heteroatoms selected from nitrogen, oxygen and sulfur hetero-atom a 5 -, 6 - or 7 - membered heteroaliphatic Ring, or

(d) a benzene ring;

R ^E、R ^FAnd R^GAre each independently a monocyclic or when there is an appropriate number of ring atoms is more Ring, saturated ring system containing from 3 to 10 ring atoms, of which at least one group selected from Nitrogen, oxygen and sulfur hetero-atom; and

R ^HContaining up to three independently selected from nitrogen, oxygen and sulfur hetero-atom a 5 - or 6 - membered heteroaromatic Ring;

Their tautomers, or tautomers of the compound or a pharmaceutically acceptable salt, solvate Or polymorph thereof.

2, A compound according to claim 1, wherein R⁶Is R^6A。

3, according to claim 1 or claim 2, wherein R¹Is R^D, Optionally By one or more R⁷Substituted.

4, A compound according to claim 3, wherein R^DIs selected from the group comprising nitrogen, oxygen and sulfur Atoms, and optionally containing in the ring up to two additional nitrogen atoms, a 5 - membered heteroaromatic ring, Or that includes 2 or 3 nitrogen atoms, 6 - membered heteroaromatic ring.

5, The compound according to claim 4, wherein R^DIs pyrazolyl, imidazolyl, isoxazolyl , Oxazolyl, oxadiazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl group.

6, according to any of claims 1 to 5, a compound wherein R⁷Is a fluoroalkyl group, a Methyl, ethyl, hydroxy, methoxy, propoxy, trifluoromethyl, oxo or CONHMe.

7, according to any of claims 1 to 6, a compound wherein R²Is hydrogen.

8, according to any of claims 1 to 7, a compound wherein R³Is hydrogen, C₁-C ₆Alkyl, optionally substituted by one or more R⁸Substituted, or R^E, Optionally substituted by one Or more R⁹Groups; wherein R^EIs a monocyclic or when there is an appropriate number of ring atoms Polycyclic, saturated ring system, which contains 3 to 7 ring atoms, of which at least one of Selected from nitrogen, oxygen and sulfur heteroatoms.

9, according to any of claims 1 to 8, a compound wherein R⁴Is hydrogen, methyl or Ethyl.

A process according to any of claims 1 to 7, a compound wherein-NR³R ⁴Constitute R^F, It is optionally substituted by one or more R¹⁰Substituted, R^FIs a monocyclic or when there appropriate amount Ring atom polycyclic, saturated ring system containing from 3 to 10 ring atoms, which contains One or two nitrogen atoms and optionally one heteroatom selected from oxygen and sulfur, the other atoms.

11, according to any of claims 1 to 10, a compound wherein R⁵Is methyl, ethyl, Group or a propyl group, each of which optionally substituted by hydroxy, methoxy or ethoxy substituted.

12, according to any of claims 1 to 11, a compound wherein R⁶Connection of the pyrazole And [4,3-d] pyrimidine ring system of N¹。

13, according to any of claims 1 to 12, a compound wherein R^6AIs a C₁-C ₄Alkyl Group or a C₁-C ₄Halogenated alkyl, each optionally substituted by C₁-C ₄Alkoxy, C₁-C ₄Haloalkoxycarbonyl Groups, (C₃-C ₆Cycloalkyl) methoxy, cyclopropyl, cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl Group or a substituted pyridyl group, or R^6ATetrahydropyranyl.

14, A compound according to claim 1, selected from:

1 - (2 - ethoxy-ethyl) -3 - methyl -5 - [(3R) -3 - methyl-piperazin-1 - yl]-N-pyrimidin-4 - Yl-1H-pyrazolo [4,3-d] pyrimidin-7 - amine,

1 - (2 - ethoxy-ethyl) -3 - ethyl -5 - [(3R) -3 - methyl-piperazin-1 - yl]-N-pyrimidin-4 - Yl-1H-pyrazolo [4,3-d] pyrimidin-7 - amine,

1 - (2 - ethoxy-ethyl) -3 - ethyl-N⁵- Methyl-N⁵- (1 - methyl-piperidin-4 - yl)-N⁷- Pyrimidine -4 - Yl-1H-pyrazolo [4,3-d] pyrimidine-5, 7 - diamine,

N-[5 - ((1R, 4R) -2,5 - diazabicyclo [2.2.1] hept-2 - yl) -1 - (2 - ethoxy-ethyl Yl) -3 - ethyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl] -4 - methyl-pyridin-2 - amine,

N-[5 - ((1S, 4S) -2,5 - diazabicyclo [2.2.1] hept-2 - yl) -1 - (2 - ethoxy-ethyl Yl) -3 - ethyl-1H-pyrazolo [4,3-d] pyrimidin-7 - yl 1-4 - methyl-pyridin-2 - amine,

N-{1 - (2 - ethoxy-ethyl) -3 - methoxy-methyl -5 - [(3R) -3 - methyl-piperazin-1 - Yl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} -6 - methyl-pyridin-2 - amine,

N-{3 - methyl -5 - [(3R) -3 - methyl-piperazin-1 - yl] -1 - [2 - (2,2,2 - trifluoroethoxy) Ethyl]-1H-pyrazolo [4,3-d] pyrimidin-7 - yl} pyrimidin-4 - yl amine,

Their tautomers, and said compounds or tautomers, pharmaceutically acceptable salt, solvate Matter and polymorphs.

15, A pharmaceutical composition which contains as claimed in any one of claim 1 to 14, to be The claimed formula (I) compound or a pharmaceutically acceptable salt, solvate or polymorph Material, and a pharmaceutically acceptable diluent or carrier.

16, use as a medicament as claimed in any one of claim 1 to 14 of the claimed formula (I) Compound or a pharmaceutically acceptable salt, solvate or polymorph thereof.

17, treatment of a mammal is known in the inhibition of PDE-5, or can be displayed may be generated Beneficial effects of obstacles or disorders, comprising administering to said mammal given treatment Effective amount of as claimed in any one of claim 1 to 14, the formula of the claimed compounds (I) or a Pharmaceutically acceptable salts, solvate or polymorph thereof.

18, as claimed in any one of claim 1 to 14, the formula of the claimed compounds (I) or A pharmaceutically acceptable salt, solvate or polymorph of the use in the pharmaceutical preparation of the Drugs used in the treatment of which are known to PDE-5 inhibition may produce or be able to produce a display Beneficial effects of disorder or illness.

19, A pharmaceutical composition which contains as claimed in any one of claim 1 to 14, to be The claimed formula (I) compound or a pharmaceutically acceptable salt, solvate or polymorph Thereof, and a second pharmaceutically active ingredient, said second pharmaceutically active ingredient selected from the following group In: aspirin, angiotensin II receptor antagonists (such as losartan, candesartan, Telmisartan, valsartan, irbesartan, and eprosartan), calcium channel blockers (eg Amlodipine), β-blockers (ie, β-adrenergic receptor antagonists, such as Sotalol Lol, propranolol, timolol, atenolol, carvedilol and metoprolol), CI1027, CCR5 receptor antagonists, imidazolines, soluble guanylate cyclase activators, diuretics (for example, Such as hydrochlorothiazide, torsemide, hydrochlorothiazide, chlorthalidone and amiloride), α-adrenergic Antagonists (eg doxazosin), ACE (angiotensin converting enzyme) inhibitors (eg chloroquine Benazepril, enalapril, ramipril, and lisinopril), aldosterone receptor antagonist (case If eplerenone and spironolactone), neutral endopeptidase inhibitors, antidiabetic agents (e.g. pancreatic Su, sulfonylureas (eg glibenclamide, glipizide and glimepiride), glitazones (case Such as rosiglitazone and pioglitazone) and metformin), cholesterol lowering agents (eg atorvastatin Atorvastatin, pravastatin, lovastatin, simvastatin, clofibrate and rosuvastatin) and α-2-δ Ligands (such as gabapentin, pregabalin, [(1R, 5R, 6S) -6 - (aminomethyl) bicyclo [3.2.0] Hept-6 - yl] acetic acid, 3 - (1 - (aminomethyl) cyclohexylmethyl)-4H-[1,2,4] oxadiazol-5 - one, C-[1 - (1H-tetrazol-5 - ylmethyl) cycloheptyl] methylamine, (3S, 4S) - (1 - amino-3 ,4 - Dimethyl - cyclopentyl)-acetic acid, (1α, 3α, 5α) - (3 - (aminomethyl) bicyclo [3.2.0] hept-3 - Yl) acetic acid, (3S, 5R) -3 - amino-5 - methyl-octanoic acid, (3S, 5R) -3 - amino-5 - methyl- Heptanoic acid, (3S, 5R) -3 - amino-5 - methyl-nonanoic acid and (3S, 5R) -3 - amino-5 - methyl-octanoic acid). ...

20, as claimed in any one of claim 1 to 14, the formula of the claimed compounds (I) or A pharmaceutically acceptable salt, solvate or polymorph with a second pharmaceutically active in the preparation of Ingredient of a medicament for combination use, the second pharmaceutically active ingredient selected from the following group: Aspirin, angiotensin II receptor antagonists (such as losartan, candesartan, for m Losartan, valsartan, irbesartan, and eprosartan), calcium channel blockers (eg amlodipine Horizon), β-blockers (ie, β-adrenergic receptor antagonists, such as sotalol, Propranolol, timolol, atenolol, carvedilol and metoprolol), CI1027, CCR5 receptor antagonists, imidazolines, soluble guanylate cyclase activators, diuretics (for example, Such as hydrochlorothiazide, torsemide, hydrochlorothiazide, chlorthalidone and amiloride), α-adrenergic Antagonists (eg doxazosin), ACE (angiotensin converting enzyme) inhibitors (eg chloroquine Benazepril, enalapril, ramipril, and lisinopril), aldosterone receptor antagonist (case If eplerenone and spironolactone), neutral endopeptidase inhibitors, antidiabetic agents (e.g. pancreatic Su, sulfonylureas (eg glibenclamide, glipizide and glimepiride), glitazones (case Such as rosiglitazone and pioglitazone) and metformin), cholesterol lowering agents (eg atorvastatin Atorvastatin, pravastatin, lovastatin, simvastatin, clofibrate and rosuvastatin) and α-2-δ Ligands (such as gabapentin, pregabalin, [(1R, 5R, 6S) -6 - (aminomethyl) bicyclo [3.2.0] Hept-6 - yl] acetic acid, 3 - (1 - (aminomethyl) cyclohexylmethyl)-4H-[1,2,4] oxadiazol-5 - one, C-[1 - (1H-tetrazol-5 - ylmethyl) cycloheptyl] methylamine, (3S, 4S) - (1 - amino-3 ,4 - Dimethyl - cyclopentyl)-acetic acid, (1α, 3α, 5α) - (3 - (aminomethyl) bicyclo [3.2.0] hept-3 - Yl) acetic acid, (3S, 5R) -3 - amino-5 - methyl-octanoic acid, (3S, 5R) -3 - amino-5 - methyl- Heptanoic acid, (3S, 5R) -3 - amino-5 - methyl-nonanoic acid and (3S, 5R) -3 - amino-5 - methyl-octanoic acid), The drug used in the treatment in which the PDE-5 inhibition known to produce or be able to show a beneficial Effect of disorder or illness. ...

Where R⁵And R⁶Is as defined in claim 1.

22, formula (VIII) Compound

Where R¹、R ²、R ⁵And R⁶Is as defined in claim 1.

23, prepared as claimed in claim 1 of formula (I) compounds, including the right as As defined in claim 22 formula (VII) with a compound of the compound HNR³R ⁴The processing procedure, in which R³And R⁴Is as defined in claim 1.